Cancer Genetics Risk Assessment and Counseling (PDQ®)–Health Professional Version - National Cancer Institute

Cancer Genetics Risk Assessment and Counseling (PDQ®)–Health Professional Version - National Cancer Institute

Cancer Genetics Risk Assessment and Counseling (PDQ®)–Health Professional Version

ON THIS PAGE

• Executive Summary
• Introduction
• Identification of Candidates for Referral to Genetic Counseling
• Cancer Risk Assessment and Counseling
• Components of the Risk Assessment Process
• The Option of Genetic Testing
• Education and Counseling About Risk/Risk Communication
• Ethical, Legal, and Social Implications
• Changes to This Summary (11/08/2019)
• About This PDQ Summary

Executive Summary

This executive summary reviews the topics covered in this PDQ summary on cancer genetics risk assessment and genetic counseling, with hyperlinks to detailed sections below that describe the evidence on each topic.

• Identification of Individuals for Cancer Genetics Risk Assessment and Counseling
  Individuals are considered to be candidates for cancer risk assessment if they have a personal and/or family history (on the maternal or paternal side) or clinical characteristics with features suggestive of hereditary cancer. These features vary by type of cancer and specific hereditary syndrome. Criteria have been published to help identify individuals who may benefit from genetic counseling. It is important that individuals who are candidates for genetic testing undergo genetic education and counseling before testing to facilitate informed decision-making and adaptation to the risk or condition. Genetic education and counseling allows individuals to consider the various medical uncertainties, diagnosis, or medical management options based on varied test results; and the risks, benefits, and limitations of genetic testing.
• Components of Cancer Genetics Risk Assessment and Counseling
  Comprehensive cancer risk assessment and counseling is a consultative service that includes clinical assessment, genetic testing when appropriate, and risk management recommendations delivered in the context of one or more genetic counseling sessions. Pretest genetic counseling is an important part of the risk assessment process and helps patients understand their genetic testing options and potential outcomes. Posttest genetic counseling helps patients understand their test results, including the medical implications for themselves and their relatives.
  The recommended provision of cancer risk assessment services optimally involves care providers from multiple disciplines, including a genetic counselor; a genetics advanced practice nurse; a medical geneticist or a physician, such as an oncologist, surgeon, or internist; and potential referrals to other specialists, such as mental health professionals, endocrinologists, and reproductive specialists.
  Traditionally, genetic counseling services have been delivered using individualized, in-person appointments. However, other methodologies are being explored, including group sessions, telephone counseling, and telemedicine by videoconferencing.
• Genetic Testing Considerations
  There are many factors that can influence an individual’s decision to undergo genetic testing and which type of test to use, including the presence of a known pathogenic variant in the family, patterns of cancer in the family, insurance coverage, family planning considerations, and the psychological impact of a test result. Previously, most germline genetic testing was offered for a single gene at a time; however, recent technological advances have resulted in the widespread availability of multigene (panel) testing, which can simultaneously test for pathogenic variants in many genes at once, often at costs comparable to single-gene testing. Research examining the use of multigene testing is under way. Some genetic tests are also offered directly to the consumer (DTC). While these tests may promote patient autonomy and increased awareness of the importance of family history, DTC genetic testing may not include genetic counseling or interpretation of the results by a genetics professional.
• Ethical, Legal, and Social Implications
  Having an understanding of the ethical, legal, and social implications regarding cancer genetic testing may influence the clinician’s response to the complex questions and issues that may arise during the process of risk assessment and counseling. The tenets of beneficence, nonmaleficence, autonomy, and justice are part of a framework needed to balance the complex and potentially conflicting factors surrounding a clinician’s role in respecting privacy, confidentiality, and fair use of genetic information obtained from cancer genetic testing.
  Employment and insurance discrimination are common concerns for individuals considering genetic testing. The Genetic Information Nondiscrimination Act, a Federal law passed in 2008, protects the provision of health insurance and employment discrimination on the basis of genetics information; however, it does not apply to members of the military or to long-term care insurance.

Introduction

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

[Note: A concerted effort is being made within the genetics community to shift terminology used to describe genetic variation. The shift is to use the term “variant” rather than the term “mutation” to describe a difference that exists between the person or group being studied and the reference sequence, particularly for differences that exist in the germline. Variants can then be further classified as benign (harmless), likely benign, of uncertain significance, likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term pathogenic variant to describe a disease-causing mutation. Refer to the Cancer Genetics Overview summary for more information about variant classification.]

This summary describes current approaches to assessing and counseling people about their chance of having an inherited susceptibility to cancer. Genetic counseling is defined by the National Society of Genetic CounselorsExit Disclaimer as the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease. Several reviews present overviews of the cancer risk assessment, counseling, and genetic testing process.[1,2]

Individuals are considered to be candidates for cancer risk assessment if they have a personal and/or family history (maternal or paternal lineage) with features suggestive of hereditary cancer.[1] These features vary by type of cancer and specific hereditary syndrome. Criteria have been published to help identify individuals who may benefit from genetic counseling.[1,3] The PDQ cancer genetics information summaries on breast, ovarian, endometrial, colorectal, prostate, kidney, and skin cancers and endocrine and neuroendocrine neoplasias describe the clinical features of hereditary syndromes associated with these conditions.

The following are features that suggest hereditary cancer:[4-8]

• Unusually early age of cancer onset (e.g., premenopausal breast cancer).
• Multiple primary cancers in a single individual (e.g., colorectal and endometrial cancer).
• Bilateral cancer in paired organs or multifocal disease (e.g., bilateral breast cancer or multifocal renal cancer).
• Clustering of the same type of cancer in close relatives (e.g., mother, daughter, and sisters with breast cancer).
• Cancers occurring in multiple generations of a family (i.e., autosomal dominant inheritance).
• Occurrence of rare tumors (e.g., retinoblastoma, adrenocortical carcinoma, granulosa cell tumor of the ovary, ocular melanoma, or duodenal cancer).
• Occurrence of epithelial ovarian, fallopian tube, or primary peritoneal cancer.
• Unusual presentation of cancer (e.g., male breast cancer).
• Uncommon tumor histology (e.g., medullary thyroid carcinoma).
• Rare cancers associated with birth defects (e.g., Wilms tumor and genitourinary abnormalities).
• Geographic or ethnic populations known to be at high risk of hereditary cancers. Genetic testing candidates may be identified based solely on ethnicity when a strong founder effect is present in a given population (e.g., Ashkenazi heritage and BRCA1/BRCA2 pathogenic variants).

As part of the process of genetic education and counseling, genetic testing may be considered when the following factors are present:[9-11]

• An individual's personal history (including ethnicity) and/or family history are suspicious for a genetic predisposition to cancer.
• The genetic test has sufficient sensitivity and specificity to be interpreted.
• The test will impact the individual's diagnosis, cancer management or cancer risk management, and/or help clarify risk in family members.

It is important that individuals who are candidates for genetic testing undergo genetic education and counseling before testing to facilitate informed decision making and adaptation to the risk or condition.[1,7-13] Genetic education and counseling allows individuals to consider the various medical uncertainties, diagnosis, or medical management based on varied test results, and the risks, benefits, and limitations of genetic testing.

References

1. Riley BD, Culver JO, Skrzynia C, et al.: Essential elements of genetic cancer risk assessment, counseling, and testing: updated recommendations of the National Society of Genetic Counselors. J Genet Couns 21 (2): 151-61, 2012. [PUBMED Abstract]
2. Weitzel JN, Blazer KR, MacDonald DJ, et al.: Genetics, genomics, and cancer risk assessment: State of the Art and Future Directions in the Era of Personalized Medicine. CA Cancer J Clin 61 (5): 327-59, 2011 Sep-Oct. [PUBMED Abstract]
3. Hampel H, Bennett RL, Buchanan A, et al.: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 17 (1): 70-87, 2015. [PUBMED Abstract]
4. Tobias DH, Eng C, McCurdy LD, et al.: Founder BRCA 1 and 2 mutations among a consecutive series of Ashkenazi Jewish ovarian cancer patients. Gynecol Oncol 78 (2): 148-51, 2000. [PUBMED Abstract]
5. Beller U, Halle D, Catane R, et al.: High frequency of BRCA1 and BRCA2 germline mutations in Ashkenazi Jewish ovarian cancer patients, regardless of family history. Gynecol Oncol 67 (2): 123-6, 1997. [PUBMED Abstract]
6. Gabai-Kapara E, Lahad A, Kaufman B, et al.: Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2. Proc Natl Acad Sci U S A 111 (39): 14205-10, 2014. [PUBMED Abstract]
7. Randall LM, Pothuri B, Swisher EM, et al.: Multi-disciplinary summit on genetics services for women with gynecologic cancers: A Society of Gynecologic Oncology White Paper. Gynecol Oncol 146 (2): 217-224, 2017. [PUBMED Abstract]
8. Committee on Practice Bulletins–Gynecology, Committee on Genetics, Society of Gynecologic Oncology: Practice Bulletin No 182: Hereditary Breast and Ovarian Cancer Syndrome. Obstet Gynecol 130 (3): e110-e126, 2017. [PUBMED Abstract]
9. Robson ME, Storm CD, Weitzel J, et al.: American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 28 (5): 893-901, 2010. [PUBMED Abstract]
10. Lancaster JM, Powell CB, Chen LM, et al.: Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol 136 (1): 3-7, 2015. [PUBMED Abstract]
11. Robson ME, Bradbury AR, Arun B, et al.: American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. J Clin Oncol 33 (31): 3660-7, 2015. [PUBMED Abstract]
12. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 3.2019. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2019. Available online with free registration.Exit Disclaimer Last accessed June 20, 2019.
13. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal. Version 2.2019. Plymouth Meeting, PA: National Comprehensive Cancer Network, 2019. Available online with free registration.Exit Disclaimer Last accessed October 15, 2019.

Identification of Candidates for Referral to Genetic Counseling

In This Section

• Tools to Identify Candidates for Genetic Counseling and Genetic Testing

After an individual’s personal and family cancer histories have been collected, several factors could warrant referral to a genetics professional for evaluation of hereditary cancer susceptibility syndromes. The American College of Medical Genetics and Genomics and the National Society of Genetic Counselors have published a comprehensive set of personal and family history criteriaExit Disclaimer to guide the identification of at-risk individuals and appropriate referral for cancer genetic risk consultation.[1] These practice guidelines take into account tumor types or other features and related criteria that would indicate a need for a genetics referral. The authors state that the guidelines are intended to maximize appropriate referral of at-risk individuals for cancer genetic consultation but are not meant to provide genetic testing or treatment recommendations.

Tools to Identify Candidates for Genetic Counseling and Genetic Testing

Identification of patients at moderate to high risk of hereditary cancer for genetic services is recommended by all major societies. Primary care physicians have a number of tools available to triage patients. In addition to the published categorical guidelines available through professional organizations,[1-4] there are also red flag cards, paper-based checklists, and patient-directed online referral tools. Table 1 provides a list of several publically available resources that can be used to identify patients for referral to genetic services. Although most tools are brief and simple enough for patients to complete on their own, either previsit, online, or in the waiting room, clinical review is warranted. Many include the commonly known features suggestive of hereditary cancers, but exclusions are noted in the table below.

Table 1. Available Tools to Identify Candidates for Referral to Genetics for Further Evaluation and Consideration of Genetic Testing

ENLARGE

Name	Mode and Length (Referral Threshold)	Sensitivity/Specificity and Validation	Tool Completed By (Tested Setting)	Featuresa
aAll tools are available in English. Tools were tested in U.S. populations unless otherwise stated.
bReferral yield in test population.
Breast/Ovarian Cancer Tools for Health Professionals
Breast cancer referral screening tool (B-RST) [5]	• Paper/OnlineExit Disclaimer	Sensitivity 81%/Specificity 92%	Health professional (mammography clinic)	Does not include bilateral breast cancer or breast and ovarian cancer in the same person. 6% high riskb.
	• 2-column table (2 positive answers)	Validated in other populations [6,7]
Family health screening questionnaire [8]	• Paper	Sensitivity 95%/Specificity 54%	Health professional (primary care)	Tested in Australia. Does not include bilateral breast cancer or breast and ovarian cancer in the same person.
	• 9 questions (1 positive answer)
Family history assessment tool (FHAT) [9]	• Paper	Not provided	Health professional (primary care)	Tested in Canada. Includes colon and prostate cancers. Includes third-degree relatives.
	• 12 questions (>10 points for family score)
FHS-7 [10]	• Paper	Sensitivity 87%/Specificity 54%	Health professional (primary care)	Tested in community-based population in Brazil. 6% high riskb.
	• 7 questions (1 positive answer)
Pedigree assessment tool (PAT) [11]	• Paper	Sensitivity 100%/Specificity 93%	Health professional (primary care)	Tested in community hospital.
	• 5 items (≥8 points)	Validated in other populations [12]
Breast/Ovarian Cancer Tools for Patients
“Are you at risk for hereditary breast cancer?” educational brochure [13]	• Paper	Not provided	Patient (breast and cervical cancer screening clinic)	Tested in underinsured or uninsured low-income women.
	• 11 questions (1 positive answer)
Family history questionnaire [14]	• Paper	Not provided	Patient (mammography clinic)	Tested in Australia. Does not include ovarian cancer, male breast cancer, or bilateral breast cancer. 13% high riskb.
	• 6 questions (about 3 positive answers)
6-point scale [15]	• Paper	Sensitivity 27%/Specificity 97%	Patient (mammography clinic)	Tested in low-income women in a safety net setting.
	• 10 questions (≥6 points)
Colon Cancer Tools
FHS-7 [10]	• Paper	Sensitivity 87%/Specificity 54%	Health professional (primary care)	Tested in community-based population in Brazil. 6% high riskb.
	• 7 questions (1 positive answer)
Lynch syndrome risk assessment tool [16]	• Paper	Not provided	Patient (colonoscopy clinic)	3% high riskb.
	• 7 questions (1 positive answer)

There are also more extensive statistical risk assessment models designed for both highly motivated patients [17,18] and genetic specialists (e.g., CancerGeneExit Disclaimer, IBISExit Disclaimer).

References

1. Hampel H, Bennett RL, Buchanan A, et al.: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 17 (1): 70-87, 2015. [PUBMED Abstract]
2. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 3.2019. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2019. Available online with free registration.Exit Disclaimer Last accessed June 20, 2019.
3. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal. Version 2.2019. Plymouth Meeting, PA: National Comprehensive Cancer Network, 2019. Available online with free registration.Exit Disclaimer Last accessed October 15, 2019.
4. Lancaster JM, Powell CB, Chen LM, et al.: Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol 136 (1): 3-7, 2015. [PUBMED Abstract]
5. Bellcross CA, Lemke AA, Pape LS, et al.: Evaluation of a breast/ovarian cancer genetics referral screening tool in a mammography population. Genet Med 11 (11): 783-9, 2009. [PUBMED Abstract]
6. Bellcross C: Further development and evaluation of a breast/ovarian cancer genetics referral screening tool. Genet Med 12 (4): 240, 2010. [PUBMED Abstract]
7. Brannon Traxler L, Martin ML, Kerber AS, et al.: Implementing a screening tool for identifying patients at risk for hereditary breast and ovarian cancer: a statewide initiative. Ann Surg Oncol 21 (10): 3342-7, 2014. [PUBMED Abstract]
8. Emery JD, Reid G, Prevost AT, et al.: Development and validation of a family history screening questionnaire in Australian primary care. Ann Fam Med 12 (3): 241-9, 2014 May-Jun. [PUBMED Abstract]
9. Gilpin CA, Carson N, Hunter AG: A preliminary validation of a family history assessment form to select women at risk for breast or ovarian cancer for referral to a genetics center. Clin Genet 58 (4): 299-308, 2000. [PUBMED Abstract]
10. Ashton-Prolla P, Giacomazzi J, Schmidt AV, et al.: Development and validation of a simple questionnaire for the identification of hereditary breast cancer in primary care. BMC Cancer 9: 283, 2009. [PUBMED Abstract]
11. Hoskins KF, Zwaagstra A, Ranz M: Validation of a tool for identifying women at high risk for hereditary breast cancer in population-based screening. Cancer 107 (8): 1769-76, 2006. [PUBMED Abstract]
12. Teller P, Hoskins KF, Zwaagstra A, et al.: Validation of the pedigree assessment tool (PAT) in families with BRCA1 and BRCA2 mutations. Ann Surg Oncol 17 (1): 240-6, 2010. [PUBMED Abstract]
13. Cohn WF, Jones SM, Miesfeldt S: "Are you at risk for hereditary breast cancer?": development of a personal risk assessment tool for hereditary breast and ovarian cancer. J Genet Couns 17 (1): 64-78, 2008. [PUBMED Abstract]
14. Fisher TJ, Kirk J, Hopper JL, et al.: A simple tool for identifying unaffected women at a moderately increased or potentially high risk of breast cancer based on their family history. Breast 12 (2): 120-7, 2003. [PUBMED Abstract]
15. Stewart SL, Kaplan CP, Lee R, et al.: Validation of an Efficient Screening Tool to Identify Low-Income Women at High Risk for Hereditary Breast Cancer. Public Health Genomics 19 (6): 342-351, 2016. [PUBMED Abstract]
16. Rabinowitz-Abrams D, Morgan D, Morse J, et al.: Building a tool to identify risk for Lynch syndrome among individuals presenting for screening colonoscopy. J Genet Couns 19 (4): 353-9, 2010. [PUBMED Abstract]
17. Sweet K, Sturm AC, Rettig A, et al.: Clinically relevant lessons from Family HealthLink: a cancer and coronary heart disease familial risk assessment tool. Genet Med 17 (6): 493-500, 2015. [PUBMED Abstract]
18. Baumgart LA, Postula KJ, Knaus WA: Initial clinical validation of Health Heritage, a patient-facing tool for personal and family history collection and cancer risk assessment. Fam Cancer 15 (2): 331-9, 2016. [PUBMED Abstract]

Cancer Risk Assessment and Counseling

In This Section

• Genetic Counseling
• Pretest Genetic Education and Counseling Outcomes
  • Modalities of genetic counseling

Comprehensive cancer risk assessment is a consultative service that includes clinical assessment, genetic testing when appropriate, and risk management recommendations delivered in the context of one or more genetic counseling sessions. Pretest genetic counseling is an important part of the risk assessment process and helps patients understand their genetic testing options and potential outcomes. Posttest genetic counseling helps patients understand their test results, including the medical implications for themselves and their relatives.

The following professional organizations emphasize the importance of genetic counseling in the cancer risk assessment and genetic testing process:

• American College of Medical Genetics and Genomics.[1]
• American College of Obstetrics and Gynecology.[2]
• American Society of Clinical Oncology.[3,4]
• American Society of Human Genetics.[5,6]
• International Society of Nurses in Genetics.[7,8]
• National Society of Genetic Counselors.[9-11]
• National Comprehensive Cancer Network.[12,13]
• Oncology Nursing Society.[14]
• Society of Gynecologic Oncologists.[15,16]
• U.S. Preventive Services Task Force.[17]

A list of organizations that have published clinical practices guidelines related to genetic counseling, risk assessment, genetic testing, and/or management for hereditary breast and ovarian cancers is available in the PDQ summary on Genetics of Breast and Gynecologic Cancers.

Genetic counseling informs the consultand about potential cancer risks and the benefits and limitations of genetic testing and offers an opportunity to consider the potential medical, psychological, familial, and social implications of genetic information.[9,18] Descriptions of genetic counseling and the specialized practice of cancer risk assessment counseling are detailed below.

Genetic Counseling

Genetic counseling has been defined by the National Society of Genetic Counselors as the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease, including the following:[9]

• How inherited diseases and conditions might affect them or their families.
• How family and medical histories may impact the chance of disease occurrence or recurrence.
• Which genetic tests may or may not be right for them, and what those tests may or may not tell.
• How to make the most informed choices about health care conditions.

Traditionally, genetic counseling services have been delivered using individualized in-person appointments. However, other methodologies have been implemented, including group sessions, telephone counseling, and online genetic counseling using remote videoconferencing, which is often referred to as telegenetics. (Refer to the Modalities of genetic counseling section of this summary for more information.)

Central to the philosophy and practice of genetic counseling are the principles of voluntary utilization of services, informed decision making, attention to psychosocial and affective dimensions of coping with genetic risk, and protection of patient confidentiality and privacy. This is facilitated through a combination of rapport building and information gathering; establishing or verifying diagnoses; risk assessment and calculation of quantitative occurrence/recurrence risks; education and informed consent processes; psychosocial assessment, support, and counseling appropriate to a family’s culture and ethnicity; and other relevant background characteristics.[19,20] The psychosocial assessment is especially important in the genetic counseling process because individuals most vulnerable to adverse effects of genetic information may include those who have had difficulty dealing with stressful life events in the past.[21] Variables that may influence psychosocial adjustment to genetic information include individual and familial factors; cultural factors; and health system factors such as the type of test, disease status, and risk information.[21] Findings from a psychosocial assessment can be used to help guide the direction of the counseling session.[10] An important objective of genetic counseling is to provide an opportunity for shared decision making when the medical benefits of one course of action are not demonstrated to be superior to another. The relationship between the availability of effective medical treatment for carriers of pathogenic variants and the clinical validity of a given test affects the degree to which personal choice or physician recommendation is supported in counseling at-risk individuals.[22] Uptake of genetic counseling services among those referred varies based on the cancer syndrome and the clinical setting. Efforts to decrease barriers to service utilization are ongoing (e.g., the use of a patient navigator or an oncology clinic–based genetic counselor may increase utilization of these services).[23-25] Readers interested in the nature and history of genetic counseling are referred to a number of comprehensive reviews.[26-31]

Pretest Genetic Education and Counseling Outcomes

Cancer risk assessment counseling has emerged as a specialized practice that requires knowledge of genetics, oncology, and individual and family counseling skills that may be provided by health care providers with this interdisciplinary training.[32] Some centers providing cancer risk assessment services involve a multidisciplinary team, which may include a genetic counselor; a genetics advanced practice nurse; a medical geneticist or a physician, such as an oncologist, surgeon, or internist; and a mental health professional.

Modalities of genetic counseling

Traditionally, genetic counseling services have been delivered using individualized in-person appointments. However, other methodologies have been implemented, including group sessions, telephone counseling, and online genetic counseling using remote videoconferencing, which is often referred to as telegenetics.[33-41] Of these alternative approaches, only telephone counseling has been examined for noninferiority against in-person genetic counseling in a randomized controlled trial.[42-45]

Telephone genetic counseling

A systematic review identified 13 published studies that used a randomized controlled trial design to compare pretest and posttest outcomes for in-person genetic counseling with telephone counseling. Knowledge and psychosocial outcomes (e.g., distress) were found to be noninferior, equivalent, or not statistically significant between telephone counseling and in-person counseling. Two studies demonstrated lower testing intention or uptake among participants receiving telephone counseling. The majority of studies also found no difference in satisfaction; however, two studies demonstrated higher satisfaction among individuals who received telephone versus in-person genetic counseling.[45] (The studies were conducted prior to the adoption of multigene panel testing.)

Another group reported results of a study where all participants (N = 1,178) received in-person pretest counseling at one of five participating sites. Those participants willing to be randomized had their results disclosed by telephone (n = 401) or in person (n = 418). Notably, 30% of participants in this study had multigene panel testing. In this trial, telephone disclosure was noninferior to in-person results disclosure when comparing primary psychosocial outcomes (e.g., general and state anxiety). In primary analysis, knowledge did not meet the threshold of noninferiority without imputing missing data. Secondary outcomes related to cancer distress, depression, uncertainty, satisfaction with genetic testing, and behavioral intentions for risk management strategies were not statistically significant between groups.[46]

Video-assisted genetic counseling

Studies have also examined the use of online genetic counseling using remote videoconferencing (telegenetics) as an alternative to in-person genetic counseling and demonstrated increases in patient knowledge, high levels of satisfaction, and minimal negative psychosocial outcomes.[47-49]

References

1. Hampel H, Bennett RL, Buchanan A, et al.: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 17 (1): 70-87, 2015. [PUBMED Abstract]
2. Committee on Practice Bulletins–Gynecology, Committee on Genetics, Society of Gynecologic Oncology: Practice Bulletin No 182: Hereditary Breast and Ovarian Cancer Syndrome. Obstet Gynecol 130 (3): e110-e126, 2017. [PUBMED Abstract]
3. Robson ME, Storm CD, Weitzel J, et al.: American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 28 (5): 893-901, 2010. [PUBMED Abstract]
4. Robson ME, Bradbury AR, Arun B, et al.: American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. J Clin Oncol 33 (31): 3660-7, 2015. [PUBMED Abstract]
5. Botkin JR, Belmont JW, Berg JS, et al.: Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents. Am J Hum Genet 97 (1): 6-21, 2015. [PUBMED Abstract]
6. Statement of the American Society of Human Genetics on genetic testing for breast and ovarian cancer predisposition. Am J Hum Genet 55 (5): i-iv, 1994. [PUBMED Abstract]
7. International Society of Nurses in Genetics: Provision of Quality Genetic Services and Care: Building a Multidisciplinary, Collaborative Approach among Genetic Nurses and Genetic Counselors. Pittsburgh, Pa: International Society of Nurses in Genetics, 2006. Available onlineExit Disclaimer. Last accessed June 24, 2019.
8. International Society of Nurses in Genetics: Genetic Counseling for Vulnerable Populations: The Role of Nursing. Pittsburgh, Pa: International Society of Nurses in Genetics, 2010. Available onlineExit Disclaimer. Last accessed June 24, 2019.
9. Resta R, Biesecker BB, Bennett RL, et al.: A new definition of Genetic Counseling: National Society of Genetic Counselors' Task Force report. J Genet Couns 15 (2): 77-83, 2006. [PUBMED Abstract]
10. Riley BD, Culver JO, Skrzynia C, et al.: Essential elements of genetic cancer risk assessment, counseling, and testing: updated recommendations of the National Society of Genetic Counselors. J Genet Couns 21 (2): 151-61, 2012. [PUBMED Abstract]
11. Berliner JL, Fay AM, Cummings SA, et al.: NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer. J Genet Couns 22 (2): 155-63, 2013. [PUBMED Abstract]
12. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 3.2019. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2019. Available online with free registration.Exit Disclaimer Last accessed June 20, 2019.
13. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal. Version 2.2019. Plymouth Meeting, PA: National Comprehensive Cancer Network, 2019. Available online with free registration.Exit Disclaimer Last accessed October 15, 2019.
14. Oncology nursing: the application of cancer genetics and genomics throughout the oncology care continuum. Oncol Nurs Forum 40 (1): 10-1, 2013. [PUBMED Abstract]
15. Lancaster JM, Powell CB, Chen LM, et al.: Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol 136 (1): 3-7, 2015. [PUBMED Abstract]
16. Randall LM, Pothuri B, Swisher EM, et al.: Multi-disciplinary summit on genetics services for women with gynecologic cancers: A Society of Gynecologic Oncology White Paper. Gynecol Oncol 146 (2): 217-224, 2017. [PUBMED Abstract]
17. Moyer VA; U.S. Preventive Services Task Force: Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 160 (4): 271-81, 2014. [PUBMED Abstract]
18. Resta RG: Defining and redefining the scope and goals of genetic counseling. Am J Med Genet C Semin Med Genet 142C (4): 269-75, 2006. [PUBMED Abstract]
19. Baty BJ, Kinney AY, Ellis SM: Developing culturally sensitive cancer genetics communication aids for African Americans. Am J Med Genet 118A (2): 146-55, 2003. [PUBMED Abstract]
20. Jenkins JF, Lea DH: Nursing Care in the Genomic Era: A Case-Based Approach. Sudbury, Mass: Jones and Bartlett Publishers, 2005.
21. Meiser B, Gaff C, Julian-Reynier C, et al.: International perspectives on genetic counseling and testing for breast cancer risk. Breast Dis 27: 109-25, 2006-2007. [PUBMED Abstract]
22. Burke W, Pinsky LE, Press NA: Categorizing genetic tests to identify their ethical, legal, and social implications. Am J Med Genet 106 (3): 233-40, 2001 Fall. [PUBMED Abstract]
23. Rahm AK, Sukhanova A, Ellis J, et al.: Increasing utilization of cancer genetic counseling services using a patient navigator model. J Genet Couns 16 (2): 171-7, 2007. [PUBMED Abstract]
24. Kentwell M, Dow E, Antill Y, et al.: Mainstreaming cancer genetics: A model integrating germline BRCA testing into routine ovarian cancer clinics. Gynecol Oncol 145 (1): 130-136, 2017. [PUBMED Abstract]
25. Kishan AU, Gomez CL, Dawson NA, et al.: Increasing Appropriate BRCA1/2 Mutation Testing: The Role of Family History Documentation and Genetic Counseling in a Multidisciplinary Clinic. Ann Surg Oncol 23 (Suppl 5): 634-641, 2016. [PUBMED Abstract]
26. Walker AP: The practice of genetic counseling. In: Baker DL, Schuette JL, Uhlmann WR, eds.: A Guide to Genetic Counseling. New York, NY: Wiley-Liss, 1998, pp 1-26.
27. Bartels DM, LeRoy BS, Caplan AL, eds.: Prescribing Our Future: Ethical Challenges in Genetic Counseling. New York, NY: Aldine De Gruyter, 1993.
28. Kenen RH: Genetic counseling: the development of a new interdisciplinary occupational field. Soc Sci Med 18 (7): 541-9, 1984. [PUBMED Abstract]
29. Kenen RH, Smith AC: Genetic counseling for the next 25 years: models for the future. J Genet Couns 4 (2): 115-24, 1995.
30. Biesecker BB: Goals of genetic counseling. Clin Genet 60 (5): 323-30, 2001. [PUBMED Abstract]
31. Weil Jon: Psychosocial Genetic Counseling. New York, NY: Oxford University Press, 2000.
32. Freedman AN, Wideroff L, Olson L, et al.: US physicians' attitudes toward genetic testing for cancer susceptibility. Am J Med Genet A 120A (1): 63-71, 2003. [PUBMED Abstract]
33. Ormond K: Recommendations for telephone counseling. J Genet Couns 9 (1): 63-71, 2000.
34. Sangha K: Assessment of the effectiveness of genetic counseling by telephone compared to a clinic visit. J Genet Couns 12 (2): 171-84, 2003.
35. Calzone KA, Prindiville SA, Jourkiv O, et al.: Randomized comparison of group versus individual genetic education and counseling for familial breast and/or ovarian cancer. J Clin Oncol 23 (15): 3455-64, 2005. [PUBMED Abstract]
36. Jenkins J, Calzone KA, Dimond E, et al.: Randomized comparison of phone versus in-person BRCA1/2 predisposition genetic test result disclosure counseling. Genet Med 9 (8): 487-95, 2007. [PUBMED Abstract]
37. Peshkin BN, Demarco TA, Graves KD, et al.: Telephone genetic counseling for high-risk women undergoing BRCA1 and BRCA2 testing: rationale and development of a randomized controlled trial. Genet Test 12 (1): 37-52, 2008. [PUBMED Abstract]
38. Zilliacus EM, Meiser B, Lobb EA, et al.: Women's experience of telehealth cancer genetic counseling. J Genet Couns 19 (5): 463-72, 2010. [PUBMED Abstract]
39. Rothwell E, Kohlmann W, Jasperson K, et al.: Patient outcomes associated with group and individual genetic counseling formats. Fam Cancer 11 (1): 97-106, 2012. [PUBMED Abstract]
40. Platten U, Rantala J, Lindblom A, et al.: The use of telephone in genetic counseling versus in-person counseling: a randomized study on counselees' outcome. Fam Cancer 11 (3): 371-9, 2012. [PUBMED Abstract]
41. Benusiglio PR, Di Maria M, Dorling L, et al.: Hereditary breast and ovarian cancer: successful systematic implementation of a group approach to genetic counselling. Fam Cancer 16 (1): 51-56, 2017. [PUBMED Abstract]
42. Schwartz MD, Valdimarsdottir HB, Peshkin BN, et al.: Randomized noninferiority trial of telephone versus in-person genetic counseling for hereditary breast and ovarian cancer. J Clin Oncol 32 (7): 618-26, 2014. [PUBMED Abstract]
43. Kinney AY, Steffen LE, Brumbach BH, et al.: Randomized Noninferiority Trial of Telephone Delivery of BRCA1/2 Genetic Counseling Compared With In-Person Counseling: 1-Year Follow-Up. J Clin Oncol 34 (24): 2914-24, 2016. [PUBMED Abstract]
44. Kinney AY, Butler KM, Schwartz MD, et al.: Expanding access to BRCA1/2 genetic counseling with telephone delivery: a cluster randomized trial. J Natl Cancer Inst 106 (12): , 2014. [PUBMED Abstract]
45. Athens BA, Caldwell SL, Umstead KL, et al.: A Systematic Review of Randomized Controlled Trials to Assess Outcomes of Genetic Counseling. J Genet Couns 26 (5): 902-933, 2017. [PUBMED Abstract]
46. Bradbury AR, Patrick-Miller LJ, Egleston BL, et al.: Randomized Noninferiority Trial of Telephone vs In-Person Disclosure of Germline Cancer Genetic Test Results. J Natl Cancer Inst 110 (9): 985-993, 2018. [PUBMED Abstract]
47. Otten E, Birnie E, Ranchor AV, et al.: Telegenetics use in presymptomatic genetic counselling: patient evaluations on satisfaction and quality of care. Eur J Hum Genet 24 (4): 513-20, 2016. [PUBMED Abstract]
48. Buchanan AH, Datta SK, Skinner CS, et al.: Randomized Trial of Telegenetics vs. In-Person Cancer Genetic Counseling: Cost, Patient Satisfaction and Attendance. J Genet Couns 24 (6): 961-70, 2015. [PUBMED Abstract]
49. Bradbury A, Patrick-Miller L, Harris D, et al.: Utilizing Remote Real-Time Videoconferencing to Expand Access to Cancer Genetic Services in Community Practices: A Multicenter Feasibility Study. J Med Internet Res 18 (2): e23, 2016. [PUBMED Abstract]

Components of the Risk Assessment Process

In This Section

• Assessment
  • Psychosocial assessment
  • Risk perception
• Clinical Evaluation
  • Personal health history
  • Physical examination
  • Family history
• Determining Cancer Risk
  • Analysis of the family history
  • Methods of quantifying cancer risk

This section provides an overview of critical elements in the cancer risk assessment process.

A number of professional guidelines on the elements of cancer genetics risk assessment and counseling are available.[1-5] Except where noted, the discussion below is based on these guidelines.

The cancer risk assessment and genetic counseling process consists of one or more consultative sessions and generally includes the following:

• A detailed, multifaceted assessment including medical, psychosocial, and family history.
• A determination of the risk of cancer and/or indication for genetic testing based on evidence of an inherited cancer syndrome.
• Education and counseling about familial/hereditary cancer risks.
• If appropriate, review of genetic testing options as well as potential limitations, risks, and benefits of testing.
• Establishment of a cancer risk management plan.
• Discussion of follow-up plans, provision of referrals, educational materials, etc.

Assessment

At the outset of the initial counseling session, eliciting and addressing the consultand's perceptions and concerns about cancer and his or her expectations of the risk assessment process helps to engage the consultand in the session. This also helps inform the provider about practical or psychosocial issues and guides the focus of counseling and strategies for risk assessment.

Psychosocial assessment

The counseling process that takes place as part of a cancer risk assessment can identify factors that contribute to the consultand's perception of cancer risk and motivations to seek cancer risk assessment and genetic testing. It can also identify potential psychological issues that may need to be addressed during or after the session, particularly after genetic testing. Information collected before and/or during the session may include the following:

• Motivations for seeking cancer risk assessment.
• Beliefs about the causes of cancer.
• Experiences with cancer and feelings, perceptions, concerns, or fears related to those experiences.
• The influence of cancer experiences and perceptions on health behaviors and cancer screening practices.
• Cultural, religious, and socioeconomic background.
• General psychological history, such as depression or anxiety, and medication use.
• Coping mechanisms.
• Support systems.

Either alone or in consultation with a mental health provider, health care providers offering cancer risk counseling attempt to assess whether there are factors suggesting risk of adverse psychological outcomes after disclosure of risk and/or genetic status.

Risk perception

Perceived risk can play an important role in an individual’s decision to participate in counseling,[6] despite the fact that perceived risk often varies substantially from statistical risk estimates.[7-9]

Clinical Evaluation

Personal health history

Consideration of the consultand's personal health history is essential in cancer risk assessment, regardless of whether the individual has a personal history of cancer. Important information to obtain about the consultand's health history includes the following:[1,3]

• Current age.
• Race, ancestry, and ethnicity.
• History of benign or precancerous tumors or polyps, surgeries, biopsies, major illnesses, medications, and reproductive history (for women, this includes age at menarche, parity, age at first live birth, age at menopause, and history of exogenous hormone use).
• Screening practices and date of last screening exams, including imaging and/or physical examinations.
• Environmental exposures.
• Past and current alcohol intake and tobacco use.
• Diet, exercise, and complementary and alternative medicine practices may also be assessed.

For consultands with a history of cancer, additional information collected includes the following:

• Site/type of primary malignancy and any metastasis or recurrence.
• Age at diagnosis.
• Pathology findings/staging.
• Prior germline genetic testing results.
• Prior tumor testing results (including genomic profiling). (Refer to the Clinical Sequencing section in the Cancer Genetics Overview PDQ summary for more information about the implications of tumor testing.)
• Treatment (e.g., surgery, chemotherapy, radiation therapy, targeted therapy), including whether genetic risk assessment may affect treatment.
• Bilaterality of disease, if applicable.
• Current surveillance plan.
• Carcinogenic exposures (e.g., alcohol and tobacco use, sun exposure, radiation exposure, asbestos exposure) or other known cancer site-specific risk factors.
• How the cancer was detected (e.g., self-exam, screening test, presenting symptoms) may also be assessed.

Physical examination

In some cases, a physical exam is conducted by a qualified medical professional to determine whether the individual has physical findings suggestive of a hereditary cancer predisposition syndrome or to rule out evidence of an existing malignancy. For example, a medical professional may look for the sebaceous adenomas seen in Muir-Torre syndrome, measure the head circumference or perform a skin exam to rule out benign cutaneous features associated with Cowden syndrome, or perform a clinical breast and axillary lymph node exam on a woman undergoing a breast cancer risk assessment.

Family history

Documenting the family history

The family history is an essential tool for cancer risk assessment. The family history can be obtained via interview or written self-report; both were found to result in equivalent information.[10] Studies suggest that paper-based family history questionnaires completed before the appointment provide accurate family history information [11] and that the use of these questionnaires is an acceptable and understandable family history collection method.[12] Both multimedia-based (e.g., Internet) and print-based (e.g., family history questionnaires) tools are currently available to gather information about family history. However, on average, print-based tools have been found to be written at lower reading grade levels than multimedia-based tools.[13] It has been reported that questionnaire-based assessments may lead to some underreporting of family history; therefore, a follow-up interview to confirm the reported information and to capture all relevant family history information may be required.[14] Collecting family history from multiple relatives in a single family has been shown to increase the number of family members reported to have cancer, compared with family history information provided by a single family member.[15]

Details of the family health history are best summarized in the form of a family tree, or pedigree. The pedigree, a standardized graphic representation of family relationships, facilitates identification of patterns of disease transmission, recognition of the clinical characteristics associated with specific hereditary cancer syndromes, and determination of the best strategies and tools for risk assessment.[16,17]

Standards of pedigree nomenclature have been established.[16,17] Refer to Figure 1 for common pedigree symbols.

ENLARGE

Figure 1. Standard pedigree nomenclature. Common symbols are used to draw a pedigree (family tree). A pedigree shows relationships between family members and patterns of inheritance for certain traits and diseases.

Refer to the paragraph below for descriptions of factors suggesting inherited cancer risk.

Documentation of a comprehensive family cancer history typically includes the following:

• A three-generation pedigree consisting of a minimum of first- and second-degree relatives on both the maternal and paternal sides of the family. Information on multiple generations helps to demonstrate inheritance patterns. Hereditary cancer can be inherited from either the maternal or paternal side of the family and is often an adult-onset disease.[18]
• Race, ancestry, and ethnicity of all grandparents. This may influence decisions about genetic testing because specific pathogenic variants in some genes are known to occur with increased frequency in some populations (founder effect).[18]
• Information about seemingly unrelated conditions, such as birth defects, atypical skin bumps, or other nonmalignant conditions of children and adults that may aid in the diagnosis of a cancer susceptibility syndrome.
• Notation of adoption, nonpaternity (the biologic father should be included in the pedigree), consanguinity, and use of assisted reproductive technology (e.g., donor egg or sperm).

A three-generation family history includes the following:

• First-degree relatives (e.g., children, brothers and sisters, and parents).
• Second-degree relatives (e.g., grandparents, aunts and uncles, nieces and nephews, grandchildren, and half-siblings).
• Third-degree relatives (e.g., first cousins, great aunts, and great uncles).
• Additional distant relatives are included if information is available, especially when there are known cancer histories among them.

For any relative with cancer, collect the following information:[19]

• Primary site of each cancer. Obtaining medical documentation of key cancers (e.g., pathology reports, clinical documents, and death certificates) is especially relevant to risk assessment and/or management recommendations. (Refer to the Accuracy of the family history section of this summary for more information.)
• Age at diagnosis for each primary cancer.
• Where the relative was diagnosed and/or treated.
• History of surgery or treatments that may have reduced the risk of cancer. For example, bilateral salpingo-oophorectomy in a premenopausal woman significantly reduces the risk of ovarian and breast cancers. This may mask underlying hereditary predisposition to these cancers.
• Current age (if living).
• Age at death and cause of death (if deceased).
• Carcinogenic exposures (e.g., alcohol and tobacco use, sun exposure, radiation exposure, asbestos exposure) or other known cancer site-specific risk factors.
• Prior germline genetic testing results.
• Prior tumor testing results (including genomic profiling).
• Other significant health problems.

For relatives not affected with cancer, collect the following information:

• Current age or age at death.
• Cause of death (if deceased).
• History of any surgeries or treatments that may have reduced the risk of cancer.
• Cancer screening practices.
• Any nonmalignant features associated with the syndrome in question.
• Carcinogenic exposures (e.g., alcohol and tobacco use, sun exposure, radiation exposure, asbestos exposure) or other known cancer site-specific risk factors.
• Prior germline genetic testing results.
• Prior tumor testing results (including genomic profiling).
• Other significant health problems.

Accuracy of the family history

The accuracy of the family history has a direct bearing on determining the differential diagnoses, selecting appropriate testing, interpreting results of the genetic tests, refining individual cancer risk estimates, and outlining screening and risk reduction recommendations. In a telephone survey of 1,019 individuals, only 6% did not know whether a first-degree relative had cancer; this increased to 8.5% for second-degree relatives.[20] However, people often have incomplete or inaccurate information about the cancer history in their family.[17,19,21-27] Patient education has been shown to improve the completeness of family history collection and may lead to more-accurate risk stratification, referrals for genetic counseling, and changes to management recommendations.[28] Confirming the primary site of cancers in the family that will affect the calculation of hereditary predisposition probabilities and/or estimation of empiric cancer risks may be important, especially if decisions about treatments such as risk-reducing surgery will be based on this family history.[23,29]

Accuracy varies by cancer site and degree of relatedness.[25,30,31] Reporting of cancer family histories may be most accurate for breast cancer [25,31] and less accurate for gynecologic malignancies [25,31] and colon cancer.[25] Self-reported family histories may contain errors and, in rare instances, could be fictitious.[23,29,31] The most reliable documentation of cancer histology is the pathology report. Verification of cancers can also be made through other medical records, tumor registries, or death certificates.

Determining Cancer Risk

Analysis of the family history

Because a family history of cancer is one of the important predictors of cancer risk, analysis of the pedigree constitutes an important aspect of risk assessment. This analysis might be thought of as a series of the following questions:

• What is the evidence that a cancer susceptibility syndrome is present in this family?
• If a syndrome is suspected, what are the differential diagnoses?
• What could make the family history difficult to interpret?
• What is the most likely mode of inheritance, regardless of whether a syndrome diagnosis can be established?
• What is the chance of a member of this family developing cancer, if an inherited susceptibility exists?
• If no recognizable syndrome is present, is there a risk of cancer based on other epidemiological risk factors?

1. What is the evidence that a cancer susceptibility syndrome is present in this family?
   The clues to a hereditary syndrome are based on pedigree analysis and physical findings. The index of suspicion is raised by the following:[18]
   • Multiple cancers in close relatives, particularly in multiple generations.
   • Early age of cancer onset (younger than age 40 to 50 y for adult-onset cancers).
   • Multiple primary cancers in a single individual.
   • Bilateral cancers.
   • Recognition of the known association between etiologically related cancers in the family (e.g., breast and ovarian cancers; colon and endometrial cancers).
   • Presence of congenital anomalies or precursor lesions that are known to be associated with increased cancer risk (e.g., presence of atypical nevi and risk of malignant melanoma).
   • Recognizable mendelian inheritance pattern.
   • Specific tumor types or pathologies associated with germline pathogenic variants in cancer susceptibility genes, regardless of family history (e.g., ovarian cancer, medullary thyroid cancer, triple-negative breast cancer, sex cord tumors in ovarian cancer). (Refer to the PDQ summaries on Genetics of Breast and Gynecologic Cancers and Genetics of Endocrine and Neuroendocrine Neoplasias for more information about these tumor types and the associated genes.)
   • Abnormal results from colon or endometrial tumor testing with microsatellite instability or immunohistochemistry, suggestive of Lynch syndrome. (Refer to the Genetics of Lynch syndrome section in the PDQ summary on Genetics of Colorectal Cancer for more information.)
   • Somatic mutations identified from tumor genomic profiling that may be present in the germline.
   Clinical characteristics associated with different cancer genetic syndromes are summarized in the following comprehensive set of personal and family history criteriaExit Disclaimer published by the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors.[32] These practice guidelines take into account tumor types or other features and related criteria that would indicate a need for a genetics referral. The authors state that the guidelines are intended to maximize appropriate referral of at-risk individuals for cancer genetic consultation but are not meant to provide genetic testing or treatment recommendations.
2. If a syndrome is suspected, what are the differential diagnoses?
   The most commonly encountered indications for genetic counseling/testing are for suspected hereditary breast cancer or hereditary colon cancer syndromes.
   For hereditary breast cancer, genetic counseling and testing criteria are broad.[32,33] Multigene panel testing has revealed that pathogenic variants in several other high- and moderate-penetrance genes other than BRCA1 and BRCA2 contribute to this phenotype, such as PALB2, CHEK2, and ATM.
   For hereditary colon cancer syndromes, differential diagnoses are based on several factors, including the number and type of colorectal polyps and histopathology of gastrointestinal and other malignancies.[34,35] However, in the absence of polyposis and rare pathologies, Lynch syndrome is frequently in the differential. Furthermore, Lynch syndrome may be in the differential diagnoses list even when there are cases of breast and/or ovarian cancer in the family that are not consistent with hereditary breast and ovarian cancer.[36,37] (Refer to the Lynch syndrome section in the PDQ summary on Genetics of Colorectal Cancer for more information.)
   Diagnostic and testing criteria exist for several rare syndromes such as Li-Fraumeni,[38] Cowden,[39,40] multiple endocrine neoplasias,[41] and familial adenomatous polyposis.[34] In some cases, pathognomonic features are also an indicator for a likely diagnosis.[39,40]
   Based on these considerations, genetic testing options may consist of limited targeted testing for pathogenic variants in one or a small number of genes, or may consist of larger gene panels.
3. What could make the family history difficult to interpret?
   Other factors may complicate recognition of basic inheritance patterns or represent different types of disease etiology.[42-44]
   Common examples of complicating factors related to family history structure include the following:
   • Small family size.
   • Incomplete information due to lack of knowledge of family history (e.g., due to adoption or lack of information about cancers in relatives).
   • Gender imbalance (e.g., few women in a family suspected of hereditary breast cancer).
   • Deaths at particularly early ages.
   • Removal of the at-risk organ, either for risk reduction or as a result of a medical condition (e.g., hysterectomy due to history of uterine fibroids or endometriosis may hamper the identification of Lynch syndrome).
   • Misattributed parentage.
   • Consanguinity.
   Genetic factors that may affect family history interpretation include:
   • Late or variable onset of disease.
   • Nonpenetrance.
   • Variable expression.
   • Genetic heterogeneity.
   • De novo pathogenic variant.
   • Mosaicism (somatic or germline).
4. What is the most likely mode of inheritance, regardless of whether a syndrome diagnosis can be established?
   The mode of inheritance refers to the way that genetic traits are transmitted in the family.
   Most commonly, inheritance patterns are established by a combination of clinical diagnosis with a compatible, but not necessarily in itself conclusive, pedigree pattern.[45] Most recognized hereditary cancer syndromes are autosomal dominant or autosomal recessive. Clues to recognizing these patterns within a pedigree are described below. (Refer to question 3, What could make the family history difficult to interpret?, for a list of situations that may complicate pedigree interpretation.)
   Autosomal dominant

   • Autosomal dominant inheritance refers to disorders that are expressed in the heterozygote (i.e., the affected person has one copy of a variant allele and one allele that is functioning normally). All the major hereditary breast/ovarian cancer syndromes including BRCA1/BRCA2, Li-Fraumeni, and Cowden, as well as the major hereditary colon cancer syndrome, Lynch syndrome, are inherited in this fashion. Autosomal dominant inheritance is characterized by the following:
     • Vertical occurrence (i.e., seen in successive generations).
     • Usually seen only on one side of the family (i.e., unipaternal or unimaternal).
     • Males and females may inherit and transmit the disorder to offspring.
     • Male-to-male transmission may be seen.
     • Offspring have a 50% chance of inheriting a pathogenic variant and a 50% chance of inheriting the normal allele.
     • The condition may appear to skip a generation due to incomplete penetrance, early death due to other causes, delayed age of onset, or paucity of males or females when the at-risk organ is gender-specific (e.g., prostate and ovary).
     • It is possible for an individual to have a genetic variant that has not previously been expressed as an autosomal dominant family history of cancer due to a variety of factors discussed above (refer to question 3).
     • It is possible for an individual to have a de novo (new) pathogenic variant. This person would be the first affected member of his or her family but could transmit this trait in the usual autosomal dominant manner to their offspring.
     • It is possible for an individual to have pathogenic variants in more than one gene associated with known autosomal dominant inherited cancer predisposition syndromes. In families showing a phenotype suggestive of more than one susceptibility syndrome, identifying such variants helps to clarify the diagnosis and determine the appropriate testing strategy in family members.[46]
   Autosomal recessive

   • Autosomal recessive inheritance refers to an inheritance pattern in which an affected person must be homozygous (i.e., carry two copies of an altered gene, one from each parent). Some well-defined cancer susceptibility syndromes with an autosomal recessive inheritance pattern include Bloom syndrome, ataxia-telangiectasia, MUTYH-associated polyposis, and Fanconi anemia. Autosomal recessive inheritance is characterized by the following:
     • Horizontal occurrence (i.e., seen in one generation only [affected siblings in the absence of affected parents]); generally not seen in successive generations.
     • Genetic variants must come from both sides of the family (i.e., biparental inheritance).
     • Parents are heterozygous carriers; each carries one variant copy of the gene and one functional copy.
     • Parents usually do not express the trait or the full syndrome; in some cases, parents may show a mild version of some features.
     • In cases of two heterozygous parents, there is a 25% risk of future offspring being affected (homozygous).
   Complex

   • Most cancers, and most familial cancers, appear to have a complex etiology. Within clinical settings, negative or uninformative genetic testing results are common. One possible explanation for these results may be that multiple factors contributed to the development of the observed cancer(s) which are not easy to pinpoint.
   • Complex or multifactorial disease inheritance is used to describe conditions caused by genetic and environmental factors. In contrast to mendelian diseases where carrying one specific pathogenic variant is associated with high likelihood for developing the disease, complex/multifactorial diseases are caused by the interaction of genes and environmental factors. Therefore, a single genetic locus is not responsible for the condition. In most cases, the effects of genetic, lifestyle, and environmental factors in aggregate determine a person’s likelihood of being affected with a condition, such as cancer.
     Clustering of cancer among relatives is common, but teasing out the underlying causes when there is no clear pattern is more difficult. With many common malignancies, such as lung cancer, an excess of cancers in relatives can be seen. These familial aggregations are seen as being due to combinations of exposures to known carcinogens, such as tobacco smoke, and to pathogenic variants in high penetrance genes or alterations in genes with low penetrance that affect the metabolism of the carcinogens in question.[47]
     The general practitioner is likely to encounter some families with a strong genetic predisposition to cancer and the recognition of cancer susceptibility may have dramatic consequences for a given individual's health and management. Although some high-risk pathogenic variants in major cancer susceptibility genes are consistent with recognizable mendelian inheritance patterns, these syndromes are rare.
5. What is the chance of a member of this family developing cancer, if an inherited susceptibility exists?
   These probabilities vary by syndrome, family, gene, and pathogenic variant, with different variants in the same gene sometimes conferring different cancer risks, or the same variant being associated with different clinical manifestations in different families. These phenomena relate to issues such as penetrance and expressivity that are discussed elsewhere.
6. If no recognizable syndrome is present, is there a risk of cancer based on other epidemiological risk factors?
   A positive family history may sometimes provide risk information in the absence of a specific genetically determined cancer syndrome. For example, the risk associated with having a single affected relative with breast or colorectal cancer can be estimated from data derived from epidemiologic and family studies. Examples of empiric risk estimates of this kind are provided in the PDQ summaries on Genetics of Breast and Gynecologic Cancers and Genetics of Colorectal Cancer.

Methods of quantifying cancer risk

The overarching goal of cancer risk assessment is to individualize cancer risk management recommendations based on personalized risk. Methods to calculate risk utilize health history information and risk factor and family history data often in combination with emerging biologic and genetic/genomic evidence to establish predictions.[48] Multiple methodologies are used to calculate risk, including statistical models, prevalence data from specific populations, penetrance data when a documented pathogenic variant has been identified in a family, mendelian inheritance, and Bayesian analysis. All models have distinct capabilities, weaknesses, and limitations based on the methodology, sample size, and/or population used to create the model. Methods to individually quantify risk encompass two primary areas: the probability of harboring a pathogenic variant in a cancer susceptibility gene and the risk of developing a specific form of cancer.[48]

Risk of harboring a pathogenic variant in a cancer susceptibility gene

The decision to offer genetic testing for cancer susceptibility is complex and can be aided in part by objectively assessing an individual's and/or family's probability of harboring a pathogenic variant.[49] Predicting the probability of harboring a pathogenic variant in a cancer susceptibility gene can be done using several strategies, including empiric data, statistical models, population prevalence data, Mendel’s laws, Bayesian analysis, and specific health information, such as tumor-specific features.[49,50] All of these methods are gene specific or cancer-syndrome specific and are employed only after a thorough assessment has been completed and genetic differential diagnoses have been established.

If a gene or hereditary cancer syndrome is suspected, models specific to that disorder can be used to determine whether genetic testing may be informative. (Refer to the PDQ summaries on the Genetics of Breast and Gynecologic Cancers; Genetics of Colorectal Cancer; or the Genetics of Skin Cancer for more information about cancer syndrome-specific probability models.) The key to using specific models or prevalence data is to apply the model or statistics only in the population best suited for its use. For instance, a model or prevalence data derived from a population study of individuals older than 35 years may not accurately be applied in a population aged 35 years and younger. Care must be taken when interpreting the data obtained from various risk models because they differ with regard to what is actually being estimated. Some models estimate the risk of a pathogenic variant being present in the family; others estimate the risk of a pathogenic variant being present in the individual being counseled. Some models estimate the risk of specific cancers developing in an individual, while others estimate more than one of the data above. (Refer to NCI's Risk Prediction Models website or the disease-specific PDQ cancer genetics summaries for more information about specific cancer risk prediction and pathogenic variant probability models.) Other important considerations include critical family constructs, which can significantly impact model reliability, such as small family size or male-dominated families when the cancer risks are predominantly female in origin, adoption, and early deaths from other causes.[42,50] In addition, most models provide gene and/or syndrome-specific probabilities but do not account for the possibility that the personal and/or family history of cancer may be conferred by an as-yet-unidentified cancer susceptibility gene.[43] In the absence of a documented pathogenic variant in the family, critical assessment of the personal and family history is essential in determining the usefulness and limitations of probability estimates used to aid in the decisions regarding indications for genetic testing.[43,49,50]

When a pathogenic variant has been identified in a family and a test report documents that finding, prior probabilities can be ascertained with a greater degree of reliability. In this setting, probabilities can be calculated based on the pattern of inheritance associated with the gene in which the pathogenic variant has been identified. In addition, critical to the application of mendelian inheritance is the consideration of integrating Bayes Theorem, which incorporates other variables, such as current age, into the calculation for a more accurate posterior probability.[1,51] This is especially useful in individuals who have lived to be older than the age at which cancer is likely to develop based on the pathogenic variant identified in their family and therefore have a lower likelihood of harboring the family pathogenic variant when compared with the probability based on their relationship to the carrier in the family.

Even in the case of a documented pathogenic variant on one side of the family, careful assessment and evaluation of the individual’s personal and family history of cancer is essential to rule out cancer risk or suspicion of a cancer susceptibility gene pathogenic variant on the other side of the family (maternal or paternal, as applicable).[52] Segregation of more than one pathogenic variant in a family is possible (e.g., in circumstances in which a cancer syndrome has founder pathogenic variants associated with families of particular ancestral origin).

Risk of developing cancer

Unlike pathogenic variant probability models that predict the likelihood that a given personal and/or family history of cancer could be associated with a pathogenic variant in a specific gene(s), other methods and models can be used to estimate the risk of developing cancer over time. Similar to pathogenic variant probability assessments, cancer risk calculations are also complex and necessitate a detailed health history and family history. In the presence of a documented pathogenic variant, cancer risk estimates can be derived from peer-reviewed penetrance data.[1] Penetrance data are constantly being refined and many genetic variants have variable penetrance because other variables may impact the absolute risk of cancer in any given patient. Modifiers of cancer risk in carriers of pathogenic variants include the variant's effect on the function of the gene/protein (e.g., variant type and position), the contributions of modifier genes, and personal and environmental factors (e.g., the impact of bilateral salpingo-oophorectomy performed for other indications in a woman who harbors a BRCA pathogenic variant).[53] When there is evidence of an inherited susceptibility to cancer but genetic testing has not been performed, analysis of the pedigree can be used to estimate cancer risk. This type of calculation uses the probability the individual harbors a genetic variant and variant-specific penetrance data to calculate cancer risk.[1]

In the absence of evidence of a hereditary cancer syndrome, several methods can be utilized to estimate cancer risk. Relative risk data from studies of specific risk factors provide ratios of observed versus expected cancers associated with a given risk factor. However, utilizing relative risk data for individualized risk assessment can have significant limitations: relative risk calculations will differ based on the type of control group and other study-associated biases, and comparability across studies can vary widely.[51] In addition, relative risks are lifetime ratios and do not provide age-specific calculations, nor can the relative risk be multiplied by population risk to provide an individual's risk estimate.[51,54]

In spite of these limitations, disease-specific cumulative risk estimates are most often employed in clinical settings. These estimates usually provide risk for a given time interval and can be anchored to cumulative risks of other health conditions in a given population (e.g., the 5-year risk by the Gail model).[51,54] Cumulative risk models have limitations that may underestimate or overestimate risk. For example, the Gail model excludes paternal family histories of breast cancer.[50] Furthermore, many of these models were constructed from data derived from predominantly white populations and may have limited validity when used to estimate risk in other ethnicities.[55]

Cumulative risk estimates are best used when evidence of other underlying significant risk factors have been ruled out. Careful evaluation of an individual's personal health and family history can identify other confounding risk factors that may outweigh a risk estimate derived from a cumulative risk model. For example, a woman with a prior biopsy showing lobular carcinoma in situ (LCIS) whose mother was diagnosed with breast cancer at age 65 years has a greater lifetime risk from her history of LCIS than her cumulative lifetime risk of breast cancer based on one first-degree relative.[56,57] In this circumstance, recommendations for cancer risk management would be based on the risk associated with her LCIS. Unfortunately, there is no reliable method for combining all of an individual's relevant risk factors for an accurate absolute cancer risk estimate, nor are individual risk factors additive.

In summary, careful ascertainment and review of personal health and cancer family history are essential adjuncts to the use of prior probability models and cancer risk assessment models to assure that critical elements influencing risk calculations are considered.[49] Influencing factors include the following:

• Differential diagnosis that is consistent with the personal and cancer family history.
• Consideration of factors that influence how informative the family history may be.
• Population that is best suited for the use of the model.
• Tumor-specific features that may be suspicious for an inherited predisposition or modify individual cancer risk predictions.
• Model-specific limitations that can overestimate or underestimate calculations.[43]

A number of investigators are developing health care provider decision support tools such as the Genetic Risk Assessment on the Internet with Decision Support (GRAIDS),[58] but at this time, clinical judgment remains a key component of any prior probability or absolute cancer risk estimation.[49]

References

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2. Robson ME, Bradbury AR, Arun B, et al.: American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. J Clin Oncol 33 (31): 3660-7, 2015. [PUBMED Abstract]
3. Berliner JL, Fay AM, Cummings SA, et al.: NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer. J Genet Couns 22 (2): 155-63, 2013. [PUBMED Abstract]
4. Lancaster JM, Powell CB, Chen LM, et al.: Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol 136 (1): 3-7, 2015. [PUBMED Abstract]
5. Committee on Practice Bulletins–Gynecology, Committee on Genetics, Society of Gynecologic Oncology: Practice Bulletin No 182: Hereditary Breast and Ovarian Cancer Syndrome. Obstet Gynecol 130 (3): e110-e126, 2017. [PUBMED Abstract]
6. Rimer BK, Schildkraut JM, Lerman C, et al.: Participation in a women's breast cancer risk counseling trial. Who participates? Who declines? High Risk Breast Cancer Consortium. Cancer 77 (11): 2348-55, 1996. [PUBMED Abstract]
7. Evans DG, Burnell LD, Hopwood P, et al.: Perception of risk in women with a family history of breast cancer. Br J Cancer 67 (3): 612-4, 1993. [PUBMED Abstract]
8. Kash KM, Holland JC, Halper MS, et al.: Psychological distress and surveillance behaviors of women with a family history of breast cancer. J Natl Cancer Inst 84 (1): 24-30, 1992. [PUBMED Abstract]
9. Davis S, Stewart S, Bloom J: Increasing the accuracy of perceived breast cancer risk: results from a randomized trial with Cancer Information Service callers. Prev Med 39 (1): 64-73, 2004. [PUBMED Abstract]
10. Kelly KM, Shedlosky-Shoemaker R, Porter K, et al.: Cancer family history reporting: impact of method and psychosocial factors. J Genet Couns 16 (3): 373-82, 2007. [PUBMED Abstract]
11. Armel SR, McCuaig J, Finch A, et al.: The effectiveness of family history questionnaires in cancer genetic counseling. J Genet Couns 18 (4): 366-78, 2009. [PUBMED Abstract]
12. Appleby-Tagoe JH, Foulkes WD, Palma L: Reading between the lines: a comparison of responders and non-responders to a family history questionnaire and implications for cancer genetic counselling. J Genet Couns 21 (2): 273-91, 2012. [PUBMED Abstract]
13. Wang C, Gallo RE, Fleisher L, et al.: Literacy assessment of family health history tools for public health prevention. Public Health Genomics 14 (4-5): 222-37, 2011. [PUBMED Abstract]
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15. Tehranifar P, Wu HC, Shriver T, et al.: Validation of family cancer history data in high-risk families: the influence of cancer site, ethnicity, kinship degree, and multiple family reporters. Am J Epidemiol 181 (3): 204-12, 2015. [PUBMED Abstract]
16. Bennett RL, Steinhaus KA, Uhrich SB, et al.: Recommendations for standardized human pedigree nomenclature. Pedigree Standardization Task Force of the National Society of Genetic Counselors. Am J Hum Genet 56 (3): 745-52, 1995. [PUBMED Abstract]
17. Bennett RL, French KS, Resta RG, et al.: Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. J Genet Couns 17 (5): 424-33, 2008. [PUBMED Abstract]
18. Lu KH, Wood ME, Daniels M, et al.: American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. J Clin Oncol 32 (8): 833-40, 2014. [PUBMED Abstract]
19. Schneider K: Collection and interpretation of cancer histories. In: Schneider KA: Counseling About Cancer: Strategies for Genetic Counseling. 2nd ed. New York, NY: Wiley-Liss, 2002, pp 129-166.
20. Wideroff L, Garceau AO, Greene MH, et al.: Coherence and completeness of population-based family cancer reports. Cancer Epidemiol Biomarkers Prev 19 (3): 799-810, 2010. [PUBMED Abstract]
21. Mitchell RJ, Brewster D, Campbell H, et al.: Accuracy of reporting of family history of colorectal cancer. Gut 53 (2): 291-5, 2004. [PUBMED Abstract]
22. Schneider KA, DiGianni LM, Patenaude AF, et al.: Accuracy of cancer family histories: comparison of two breast cancer syndromes. Genet Test 8 (3): 222-8, 2004. [PUBMED Abstract]
23. Douglas FS, O'Dair LC, Robinson M, et al.: The accuracy of diagnoses as reported in families with cancer: a retrospective study. J Med Genet 36 (4): 309-12, 1999. [PUBMED Abstract]
24. Sijmons RH, Boonstra AE, Reefhuis J, et al.: Accuracy of family history of cancer: clinical genetic implications. Eur J Hum Genet 8 (3): 181-6, 2000. [PUBMED Abstract]
25. Mai PL, Garceau AO, Graubard BI, et al.: Confirmation of family cancer history reported in a population-based survey. J Natl Cancer Inst 103 (10): 788-97, 2011. [PUBMED Abstract]
26. Ozanne EM, O'Connell A, Bouzan C, et al.: Bias in the reporting of family history: implications for clinical care. J Genet Couns 21 (4): 547-56, 2012. [PUBMED Abstract]
27. Brennan P, Claber O, Brennan T: Cancer family history triage: a key step in the decision to offer screening and genetic testing. Fam Cancer 12 (3): 497-502, 2013. [PUBMED Abstract]
28. Beadles CA, Ryanne Wu R, Himmel T, et al.: Providing patient education: impact on quantity and quality of family health history collection. Fam Cancer 13 (2): 325-32, 2014. [PUBMED Abstract]
29. Evans DG, Kerr B, Cade D, et al.: Fictitious breast cancer family history. Lancet 348 (9033): 1034, 1996. [PUBMED Abstract]
30. Qureshi N, Wilson B, Santaguida P, et al.: Collection and Use of Cancer Family History in Primary Care. Evidence Report/Technology Assessment No. 159. Rockville,Md: Agency for Healthcare Research and Quality, 2007. AHRQ Pub No. 08-E001.
31. Murff HJ, Spigel DR, Syngal S: Does this patient have a family history of cancer? An evidence-based analysis of the accuracy of family cancer history. JAMA 292 (12): 1480-9, 2004. [PUBMED Abstract]
32. Hampel H, Bennett RL, Buchanan A, et al.: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 17 (1): 70-87, 2015. [PUBMED Abstract]
33. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 3.2019. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2019. Available online with free registration.Exit Disclaimer Last accessed June 20, 2019.
34. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal. Version 2.2019. Plymouth Meeting, PA: National Comprehensive Cancer Network, 2019. Available online with free registration.Exit Disclaimer Last accessed October 15, 2019.
35. Spoto CPE, Gullo I, Carneiro F, et al.: Hereditary gastrointestinal carcinomas and their precursors: An algorithm for genetic testing. Semin Diagn Pathol 35 (3): 170-183, 2018. [PUBMED Abstract]
36. Roberts ME, Jackson SA, Susswein LR, et al.: MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer. Genet Med 20 (10): 1167-1174, 2018. [PUBMED Abstract]
37. Espenschied CR, LaDuca H, Li S, et al.: Multigene Panel Testing Provides a New Perspective on Lynch Syndrome. J Clin Oncol 35 (22): 2568-2575, 2017. [PUBMED Abstract]
38. Bougeard G, Renaux-Petel M, Flaman JM, et al.: Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. J Clin Oncol 33 (21): 2345-52, 2015. [PUBMED Abstract]
39. Pilarski R, Eng C: Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet 41 (5): 323-6, 2004. [PUBMED Abstract]
40. Eng C: PTEN Hamartoma Tumor Syndrome (PHTS). In: Pagon RA, Adam MP, Bird TD, et al., eds.: GeneReviews. Seattle, Wash: University of Washington, 1993-2018, pp. Available online. Last accessed June 07, 2019.
41. Brandi ML, Gagel RF, Angeli A, et al.: Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86 (12): 5658-71, 2001. [PUBMED Abstract]
42. Weitzel JN, Lagos VI, Cullinane CA, et al.: Limited family structure and BRCA gene mutation status in single cases of breast cancer. JAMA 297 (23): 2587-95, 2007. [PUBMED Abstract]
43. Kauff ND, Offit K: Modeling genetic risk of breast cancer. JAMA 297 (23): 2637-9, 2007. [PUBMED Abstract]
44. Kramer JL, Velazquez IA, Chen BE, et al.: Prophylactic oophorectomy reduces breast cancer penetrance during prospective, long-term follow-up of BRCA1 mutation carriers. J Clin Oncol 23 (34): 8629-35, 2005. [PUBMED Abstract]
45. Harper PS: Practical Genetic Counselling. 3rd ed. London: Wright, 1988.
46. Whitworth J, Skytte AB, Sunde L, et al.: Multilocus Inherited Neoplasia Alleles Syndrome: A Case Series and Review. JAMA Oncol 2 (3): 373-9, 2016. [PUBMED Abstract]
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48. Freedman AN, Seminara D, Gail MH, et al.: Cancer risk prediction models: a workshop on development, evaluation, and application. J Natl Cancer Inst 97 (10): 715-23, 2005. [PUBMED Abstract]
49. Lindor NM, Lindor RA, Apicella C, et al.: Predicting BRCA1 and BRCA2 gene mutation carriers: comparison of LAMBDA, BRCAPRO, Myriad II, and modified Couch models. Fam Cancer 6 (4): 473-82, 2007. [PUBMED Abstract]
50. Domchek SM, Eisen A, Calzone K, et al.: Application of breast cancer risk prediction models in clinical practice. J Clin Oncol 21 (4): 593-601, 2003. [PUBMED Abstract]
51. Offit K, Brown K: Quantitating familial cancer risk: a resource for clinical oncologists. J Clin Oncol 12 (8): 1724-36, 1994. [PUBMED Abstract]
52. Apicella C, Andrews L, Hodgson SV, et al.: Log odds of carrying an Ancestral Mutation in BRCA1 or BRCA2 for a Defined personal and family history in an Ashkenazi Jewish woman (LAMBDA). Breast Cancer Res 5 (6): R206-16, 2003. [PUBMED Abstract]
53. Chenevix-Trench G, Milne RL, Antoniou AC, et al.: An international initiative to identify genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA). Breast Cancer Res 9 (2): 104, 2007. [PUBMED Abstract]
54. Hoskins KF, Stopfer JE, Calzone KA, et al.: Assessment and counseling for women with a family history of breast cancer. A guide for clinicians. JAMA 273 (7): 577-85, 1995. [PUBMED Abstract]
55. Adams-Campbell LL, Makambi KH, Palmer JR, et al.: Diagnostic accuracy of the Gail model in the Black Women's Health Study. Breast J 13 (4): 332-6, 2007 Jul-Aug. [PUBMED Abstract]
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57. Chuba PJ, Hamre MR, Yap J, et al.: Bilateral risk for subsequent breast cancer after lobular carcinoma-in-situ: analysis of surveillance, epidemiology, and end results data. J Clin Oncol 23 (24): 5534-41, 2005. [PUBMED Abstract]
58. Emery J, Morris H, Goodchild R, et al.: The GRAIDS Trial: a cluster randomised controlled trial of computer decision support for the management of familial cancer risk in primary care. Br J Cancer 97 (4): 486-93, 2007. [PUBMED Abstract]

The Option of Genetic Testing

In This Section

• Factors to Consider When Offering Testing
  • Indications for testing
  • Value of testing an affected family member first
  • Testing in families with a documented pathogenic variant
  • Insurance coverage
  • Genetic testing and assisted reproductive technology
• Determining the Test to Be Used
  • Multigene (panel) testing
  • Regulation of genetic tests
• Direct-to-Consumer (DTC) Genetic Tests
  • Genotyping for carrier status and disease risks
  • Genotyping for founder pathogenic variants in BRCA1 and BRCA2
  • Testing for SNPs
  • DTC whole-exome/genome sequencing and interpretation
  • Considerations
• Informed Consent
  • Core elements of informed consent
  • Testing in children
  • Testing in vulnerable populations
• Importance of Pretest Counseling
• Psychological Impact of Genetic Information/Test Results on the Individual
  • Psychological Impact of Genetic Information/Test Results on the Family

Factors to Consider When Offering Testing

Indications for testing

Experts recommend offering genetic testing when a risk assessment suggests the presence of an inherited cancer syndrome for which specific genes have been identified. The American Society of Clinical Oncology (ASCO) Policy Statement on Genetic Testing for Cancer Susceptibility proposes that genetic testing be offered when the following conditions apply:[1,2]

• An individual has a personal or family history suggestive of a genetic cancer susceptibility syndrome.
• The results of the test can be interpreted.
• Testing will influence medical management.

Characteristics used in making this determination are discussed in the PDQ summaries on the genetics of specific cancers. Even when individual and family history characteristics indicate a possible inherited cancer syndrome, individuals may elect not to proceed with testing after discussion of potential risks, benefits, and limitations, as discussed below. Conversely, individuals whose pedigrees are incomplete or uninformative due to very small family size, early deaths, or incomplete data on key family members may elect to pursue genetic testing in an attempt to better define their risk status. In these situations, it is particularly important that the pretest counseling fully explore the limitations of the testing process.

ASCO's 2010 and 2015 policy statements addressed testing for low- to moderate-penetrance genes and direct-to-consumer testing.[1,2]

ASCO’s position is that when a test, regardless of clinical utility, is ordered by a health care professional, the provider is responsible for organizing follow-up care based on the findings. For tests that were ordered by the consumer without health care professional involvement, management decisions are based on the evidence for clinical utility. For tests with accepted clinical utility, follow-up care can be guided by the evidence for cancer risk associated with the genetic test finding. However, in tests ordered by the consumer that have uncertain clinical utility, ASCO recommends that follow-up care consist of education regarding the lack of evidence regarding the test's clinical utility and that cancer risk management decisions be guided by established cancer risk factors.[1,2]

In 2015, ASCO updated its policy to address the challenges of new technologies in cancer genetics, including multigene (panel) testing for cancer genetic susceptibility, as well as incidental germline findings from somatic mutation profiling.[2] ASCO's statement expressed support for communicating medically relevant germline findings discovered in the context of somatic mutation profiling.[2]

Genetic education and counseling, including the interpretation of genetic test results, will vary depending on whether a previous attempt at genetic testing has been made (refer to Figure 2). In general, there are two primary circumstances in which genetic testing is performed:

• Families with evidence of an inherited susceptibility that have not had any genetic testing or in which genetic testing has not identified a pathogenic variant.
• Families with a documented pathogenic variant.

ENLARGE

Figure 2. This genetic testing algorithm depicts the multistep process of testing for cancer susceptibility.

Value of testing an affected family member first

Genetic susceptibility testing generally yields the most useful information when a living family member affected with the cancer of concern is tested first to determine whether a genetic basis for the cancer diagnosis can be established. If testing is deferred while follow-up with an affected relative is pending, consider providing interim cancer risk management guidelines to the unaffected proband.[3] Three possible outcomes of testing include the following (refer to Figure 2):

• Pathogenic variant detected.
• No variant detected.
• Variant of uncertain significance (VUS) detected.

If a documented pathogenic variant (associated with cancer risk) is identified, risks are based on penetrance data for pathogenic variants of that specific gene. In addition, other family members may be tested for the presence or absence of this specific pathogenic variant. If no variant is found in an affected family member, testing is considered uninformative and thus there is no basis for testing unaffected relatives. Failure of the laboratory to detect a pathogenic variant in an affected family member does not rule out an inherited basis for the cancer in that family. Reasons why testing could be uninformative include the following:

• The cancer in the family may be associated with a cancer susceptibility gene other than the gene that was tested.
• The cancer in the family may be associated with a pathogenic variant, but the cancer in the specific family member who underwent testing is not associated with that variant. This can occur especially with cancers that are common in the general population, such as breast cancer or prostate cancer. The family member who is affected with the disease but is not a carrier of the pathogenic variant associated with the inherited predisposition to cancer in the family is considered a phenocopy.
• Identifying a genetic variant may not be possible given the limited sensitivity of the laboratory techniques used to detect genetic variants. There may be additional testing available to detect certain types of variants that would have been missed by the initial genetic test.
• The function of the gene could be altered by a pathogenic variant in a different gene.

Lastly, testing may reveal a VUS. This result means that a genetic variant has been found; however, the extent that this variant increases cancer risk, or whether it is associated with the history of cancer in the family, is uncertain. In this circumstance, some clues as to the significance of the variant can be derived from the following:

• The location of the variant in relation to regions and function of a gene.
• The specific change; since many variants are missense variants, not all amino acid substitutions are as significant.
• Whether the variant has been documented in the presence of a documented pathogenic variant.
• Whether the variant is associated with the branch in the family with the cancer and/or whether the variant tracks with the cancers in the family.

Unfortunately, even with this information, there is often insufficient evidence to document the significance of a specific variant, and further clarifying research is required.

If there is no close, living, affected relative to undergo testing, or the living affected relative declines testing, other options may be discussed with the patient and the testing laboratory. In rare instances, if proper authorization is secured from the family, testing the stored tissue of a deceased relative may be considered. However, genetic tests done on stored tissue are technically difficult and may not yield a definitive result. Therefore, testing an unaffected person without prior testing of an affected family member may be performed. In these instances, counseling includes discussing that a negative test result does not rule out the presence of a cancer susceptibility gene in the family or in the patient and may be uninformative.

Testing in families with a documented pathogenic variant

Genetic susceptibility testing for a documented pathogenic variant in the family can be very informative and will yield one of the following two results (refer to Figure 2):

• Positive for the familial pathogenic variant.
• Negative for the familial pathogenic variant.

If the familial pathogenic variant is detected in a family member, their cancer risks are based on penetrance data for pathogenic variants in that specific gene. If the documented pathogenic variant is not found in a family member, the risk of cancer in that individual is equivalent to cancer risk in the general population. However, other risk factors and family history from the side of the family not associated with the documented pathogenic variant may increase the cancer risk above the general population levels.

In summary, genetic education and counseling includes identifying the most informative person in the family to test, which may be an affected family member rather than the individual seeking genetic services. In addition, counseling includes a discussion of the limitations of the test, all possible test outcomes, and the consequences of identifying a VUS.[4]

Insurance coverage

Insurance coverage varies for cancer susceptibility testing, including multigene (panel) testing. In general, most individuals who meet specific criteria (e.g., National Comprehensive Cancer Network [NCCN] guidelines for BRCA1/BRCA2 or Lynch syndrome testing) are able to obtain insurance coverage for multigene testing.[5] Of note, some insurance companies have contracts with specific laboratories through which testing must be ordered.

The Affordable Care Act (ACA) requires that private insurers cover—with no out-of-pocket costs to the insured—genetic counseling and BRCA1/BRCA2 testing for unaffected women meeting United States Preventive Services Task Force guidelines.[6,7] Importantly, under ACA guidelines, women with a prior cancer diagnosis are not covered. The ACA does not stipulate that follow-up care based on genetic test results be covered (e.g., risk-reducing surgeries). However, some insurance companies require that pretest genetic counseling be performed by a credentialed genetics provider before testing is authorized. Before testing is ordered, it is important to verify costs and insurance coverage, including for Medicaid and Medicare patients. Medicare does not cover genetic testing if the patient has not had a cancer diagnosis associated with the pathogenic variants for which testing is ordered. In addition, unaffected individuals with Medicare are not covered for testing, even if they are tested for only a known familial pathogenic variant. Further, Medicare does not cover genetic counseling as a separately billable service.[8] For individuals without insurance coverage and the underinsured, some laboratories offer low-cost options or have financial assistance programs.

Genetic testing and assisted reproductive technology

There is a risk of carriers passing on cancer-associated pathogenic variants to offspring. When an individual tests positive for one pathogenic variant in a cancer susceptibility gene, counseling about reproductive implications addresses not only the risks associated with autosomal dominant inheritance but also the potential risks of having a child with two pathogenic variants in the same gene (biallelic) that could result in a severe condition.

Assisted reproductive technology can be used for preimplantation genetic testing (PGT) and for prenatal cancer predisposition genetic testing using chorionic villus sampling and amniocentesis.[9-11] For individuals with autosomal dominant cancer syndromes (e.g., those associated with APC, BRCA1/BRCA2, PTEN, or TP53 pathogenic variants), reproductive options exist for prenatal testing and PGT to detect offspring with one copy of the pathogenic variant (heterozygotes).

In some cases (e.g., carriers of germline pathogenic variants in ATM, BLM), assessing an individual’s partner's risk for carrying a pathogenic variant associated with a dominant or recessive syndrome (i.e., his or her personal and family history and ethnicity) is indicated. In the unlikely event that both parents are heterozygous for specific pathogenic variants, there is a 25% risk that a child will be homozygous and could have a severe phenotype. In light of this information, couples may consider PGT or prenatal testing.

A proposed analytic framework for counseling carriers about reproduction options includes consideration of the following issues:[10]

1. Does the cancer syndrome include childhood malignancies or significant morbidity or mortality at an early age?
2. What is the penetrance associated with the genetic variant?
3. How severe is the syndrome phenotype?
4. Are there interventions available that decrease the pathogenic variant-associated cancer risk or are proven to detect cancer early when it is in a treatable form?
5. Is there evidence of a different phenotype if an individual is a heterozygous or homozygous carrier?[12,13]

In a study of 320 patients with different hereditary cancer syndromes, most were unaware of PGT; however, the majority expressed interest in learning more about the availability of PGT.[14] Patients also preferred having a discussion about PGT with their genetic counselor or primary physician. Disease-specific factors (e.g., severity of the hereditary condition, quality of life, and medical interventions) and individual factors (e.g., gender, childbearing status, and religious beliefs) affected patient attitudes about PGT.

Determining the Test to Be Used

Genetic testing is highly specialized. There are also multiple molecular testing methods available, each with its own indications, costs, strengths, and weaknesses. Depending on the method employed and the extent of the analysis, different tests for the same gene will have varying levels of sensitivity and specificity. Even assuming high analytic validity, genetic heterogeneity makes test selection challenging. A number of different genetic syndromes may underlie the development of a particular cancer type. For example, hereditary colorectal cancer may be due to familial adenomatous polyposis (FAP), Lynch syndrome, Peutz-Jeghers syndrome, juvenile polyposis syndrome, or other syndromes. Each of these has a different genetic basis. In addition, different genes may be responsible for the same condition (e.g., Lynch syndrome can be caused by pathogenic variants in one of several mismatch repair [MMR] genes).

In some genes, the same pathogenic variant has been found in multiple, apparently unrelated families. This observation is consistent with a founder effect, wherein a pathogenic variant identified in a contemporary population can be traced back to a small group of founders isolated by geographic, cultural, or other factors. For example, two specific BRCA1 pathogenic variants (68_69delAG and 5266dup, also known in the literature as 185delAG and 5382insC) and one BRCA2 pathogenic variant (5946delT, also known as 6174delT) have been reported to be common in Ashkenazi Jews. Other genes also have reported founder pathogenic variants. The presence of founder pathogenic variants has practical implications for genetic testing. Many laboratories offer directed testing specifically for ethnic-specific alleles. This greatly simplifies the technical aspects of the test but is not without limitations. For example, approximately 15% of BRCA1 and BRCA2 pathogenic variants that occur among Ashkenazim are nonfounder pathogenic variants.[15] Also, for genes in which large genome rearrangements are common in the founder population, ordering additional testing using different techniques may be needed.

Allelic heterogeneity (i.e., different variants within the same gene) can confer different risks or be associated with a different phenotype. For example, though the general rule is that adenomatous polyposis coli (APC) pathogenic variants are associated with hundreds or thousands of colonic polyps and colon cancer of the classical FAP syndrome, some APC pathogenic variants cause a milder clinical picture, with fewer polyps and lower colorectal cancer risk.[16,17] In addition, other disorders may be part of the FAP spectrum. Pathogenic variants in a certain portion of the APC gene also predispose to retinal changes, for example, when pathogenic variants in a different region of APC predispose to desmoid tumors.

In light of the heterogeneity in presentation and potential overlap in phenotypes among the various hereditary cancer syndromes, the selection of the appropriate genetic test for a given individual requires knowledge of genetic syndromes, molecular diagnostic methods used for identifying pathogenic variants, correlation between clinical and molecular findings, and access to information about rapidly changing testing options. These issues are addressed in detail in PDQ summaries on the genetics of specific cancers. (Refer to the PDQ summaries on Genetics of Breast and Gynecologic Cancers; Genetics of Colorectal Cancer; Genetics of Endocrine and Neuroendocrine Neoplasias; Genetics of Skin Cancer; Genetics of Kidney Cancer [Renal Cell Cancer]; and Genetics of Prostate Cancer for more information.)

Multigene (panel) testing

Next-generation sequencing (NGS) and the removal of most patent barriers to diagnostic DNA sequencing [18] have resulted in the availability of multigene testing, which can simultaneously test more than 50 genes for pathogenic variants, often at costs comparable to single-gene testing. These multigene panels can include genes with pathogenic variants that are associated with high risks of cancer and genes that confer moderate and uncertain risks. The multigene panels can be limited to specific cancer types (e.g., breast, ovarian, colon) or can include many cancer types. This type of testing has both advantages and disadvantages, and much of the information presented in this section is not based on empirical data but rather on commentaries.

Genetic education and counseling for multigene testing

ASCO has stressed the importance of genetic counseling to ensure patients are adequately informed about the implications of this type of testing and recommends that tests be ordered by cancer genetic professionals.[2,19] Yet, the use of multigene testing requires modification of traditional approaches to genetic counseling.[20,21] Optimal evidence-based counseling strategies have not yet been established. Unlike in-person, single-gene pretest genetic counseling models, these approaches have not been examined for outcomes of counseling such as comprehension, satisfaction, psychosocial outcomes, and testing uptake. Table 2 summarizes recommendations from ASCO on elements of pretest genetic counseling and informed consent for germline cancer genetic testing.[2]

Table 2. Elements of Pretest Genetic Counseling and Informed Consent for Germline Cancer Genetic Testinga

Topic	Traditional Germline Cancer Genetic Testing	Multigene Panel Germline Cancer Genetic Testing
aAdapted from Robson et al.[2]
Gene Information	Specific gene(s) or gene variant(s) being tested.	Review of specific genes included in a multigene panel may need to be batched because it is not feasible to individually cover each gene.
	Risks associated with the gene(s) or gene variants(s) and implications for health care.	Describe high-penetrance gene(s) and/or syndromes included in the multigene panel (i.e., hereditary breast-ovarian syndrome, Lynch syndrome, hereditary diffuse gastric cancer, Li-Fraumeni syndrome), possible detection based on personal and family history and general implications for health care.
		Describe generally genes of uncertain clinical utility.
Possible Test Outcomes	• Pathogenic variant detected.
	• No variant detected.
	• Variant of uncertain significance (VUS) detected.
		Variant in a gene for which there is:
		• Limited evidence regarding penetrance.
		• Discordant findings (pathogenic variant identified in a gene that is inconsistent with the patient's personal and/or family history).
		Increased rate of VUS.
Risks, Benefits, and Limitations of Genetic Testing	Psychosocial implications of test results.
	Confidentiality considerations, including privacy, data security, and placement of results (i.e., electronic health record).
	Use of DNA sample(s) for future research.
	Employment and insurance discrimination risks and protections.
	Costs involved in testing and scope of insurance coverage if applicable.
	Whether the genetic health care professional is employed by the testing company.
Implications of Genetic Testing for Family Members	Pattern of variant transmission and risks of inheritance in children and other family members.
	Importance of sharing test results with family members.
	Possible reproductive implications associated with pathogenic variants in genes associated with recessive conditions (i.e., ATM, Fanconi anemia [BRCA2, PALB2], NBN, BLM).
Use of Genetic Test Results	Implications of genetic test results on health care.

Research examining multigene testing

The range of results from NGS multigene panels is emerging in both data from clinical and laboratory series. Several of the studies are collaborations between the two. There are several important caveats about the research that has been conducted so far with regard to multigene testing:

• The studies differ in their aims, approaches, ascertainment of subjects, and panels used.
• Laboratory- and clinic-based studies likely differ with regard to their sampling frames (the population a study draws from and its characteristics). For example, some studies may include testing by a wide variety of health care professionals, some of whom may not be as experienced in triaging, testing, and advising high-risk patients.[22]
• Testing methodologies also differ among laboratories regarding exon/intron coverage, read depth, Sanger sequencing confirmation, and variant interpretation.[23]
• The genes to be tested as part of a multigene panel are constantly changing. In some studies, the composition of multigene panels changed during the course of the study, usually to include more genes.[24]
• Some patient populations included a mix of patients already tested by traditional single-gene methods and those undergoing testing for the first time, making it difficult to establish true diagnostic yield.[25,26]
• In the studies that replicated previous BRCA testing with a panel, the analytic validity of the NGS multigene panel tests is equivalent to the former single-gene tests, with almost 100% concordance in patients who had both single-gene BRCA testing and multigene testing.[25,26]

In high-risk individuals who meet criteria for hereditary cancer genetic testing but in whom no pathogenic variant was identified from single-gene testing, panel testing may identify other clinically actionable variants.[27,28] For example, the additional yield of multigene testing in individuals in whom a BRCA1/BRCA2 pathogenic variant was not detected currently seems to be approximately 4%.[26,29,30] The most common non-BRCA pathogenic variants found are in CHEK2, ATM, and PALB2.[26,29-31] In some cases, the identification of pathogenic variants from panel testing resulted in additional recommendations for screening and risk reduction beyond what would have been indicated based on family history alone.[30,32-34]

Selected reports from 2014 to 2018, which included 1,000 to 10,000 tested individuals, showed variation in pathogenic variant and VUS rates.[23,24,26,30,35-38] Pathogenic variant rates ranged from 7% to 14%; VUS rates ranged from 19% to 41% and increased with the number of genes included on the panel, but decreased in the later studies, likely because of larger data pools and refinements in variant interpretation. Additionally, VUS rates were higher in non-white individuals, likely because of the limited availability of test result data needed for accurate determination of risk.[38]

A large study published by a commercial laboratory included more than 252,000 individuals who were tested with a 25-gene panel between 2013 and 2016.[39] The study reported an overall pathogenic variant rate of 6.7% (9.8% in affected individuals and 4.7% in unaffected individuals), with an overall VUS rate of 30%. The study population was 97% female, had no prior cancer genetic testing, and 93% met NCCN criteria for hereditary breast and ovarian cancer (HBOC) or Lynch syndrome testing. It was noted that half of the pathogenic variants found for HBOC or Lynch syndrome were not in the expected genes associated with these syndromes (BRCA1, BRCA2, MLH1, MSH2, MSH6, and PMS2).

Outcomes of multigene testing

Results from multigene tests have several possible outcomes, including the following:[19]

• No variant detected.
• VUS detected.
• Pathogenic variant in a high-penetrance gene concordant with the existing personal/family history (e.g., a germline MSH2 pathogenic variant in an individual who meets Amsterdam criteria for Lynch syndrome).
• Pathogenic variant in a high-penetrance gene discordant with the existing personal/family history (e.g., a germline CDH1 pathogenic variant in an individual with no personal/family history of gastric cancer).
• Pathogenic variant in a moderate-penetrance gene (e.g., CHEK2, ATM).
• Pathogenic variant in a gene with uncertain cancer risks and/or cancer associations.

Results can also reveal more than one finding given that multiple genes are being tested simultaneously and the elevated rate of VUS.[21] There has been no assessment of outcomes of multigene tests such as comprehension, psychosocial outcomes, and uptake of cancer risk management options.

Considerations when using multigene testing

Utilizing multigene panels can be complex but may offer advantages over sequential testing strategies. First, in some types of cancer, several genes can be associated with specific phenotypes; therefore, testing for all genes associated with a given phenotype can save both time and money.[40] Additionally, multigene testing may help identify the genetic basis for cancer in families in whom the differential diagnosis includes multiple syndromes or when the family history does not meet standard criteria for a single cancer syndrome.[21,40] (Refer to the Analysis of the family history section of this summary for a list of factors that may make a family history difficult to interpret.)

However, there can be challenges to employing this testing approach. Clinical laboratories now offer a varying array of clinical cancer susceptibility gene panels.[41,42] Multigene panels continue to evolve, and the genes included on the panels can change. Other challenges of interpreting multigene test results include higher rates of VUS than with single-gene testing (the rate of VUS increases with the number of genes tested),[24] higher rates of VUS in some minority populations,[32,43] and the detection of variants in genes associated with uncertain cancer risks.

In addition to these primary challenges, providers deciding the optimal testing strategy may also consider the following: the overall expense and out-of-pocket expense to the patient; insurance reimbursement; time frame to complete the test; ease of laboratory use for the clinician ordering testing; the probability of identifying a VUS and management of those findings, such as the reclassification process and provision of supplemental data regarding the variant; technical differences, such as the presence of a deletion/duplication assay; patient preference; and clinical history.[2,40,41,44]

Overall, there is insufficient evidence to determine superiority of multigene testing over phenotype-guided testing or sequential gene testing.[19] As a consequence, practice guidelines for optimal clinical use of multigene tests continue to evolve.[2,45] The NCCN and ASCO guidelines suggest that efficiencies may be gained by using multigene testing when there is more than one cancer syndrome or gene on the differential diagnosis list.[2,45] Additionally, NCCN states that there may be a role for multigene testing when a patient has a personal or family history that is consistent with an inherited susceptibility but single-gene testing has not identified a pathogenic variant.[45]

Another important consideration is that multigene tests may include genes in which pathogenic variants are associated with moderate or uncertain penetrance. Management of individuals with pathogenic variants in such genes can present additional challenges, particularly when expert consensus or evidence-based recommendations are not available. (Refer to Figure 1 in the Cancer Genetics Overview PDQ summary for information about moderate and low penetrance.) Moreover, there may be limited or no evidence to support changes to medical management based on the level of risk or uncertain risk; however, management may still be affected by family history.[1,2] A framework for clinical management incorporates emerging data on age-specific, lifetime, and absolute cancer risks conferred by pathogenic variants in several moderate-risk genes.[46] (Refer to the Penetrance of Inherited Susceptibility to Hereditary Breast and/or Gynecologic Cancers section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about this framework.)

Regulation of genetic tests

Government regulation of genetic tests to date remains extremely limited in terms of both analytic and clinical validity with little interagency coordination.[47] The Centers for Medicare & Medicaid Services, using the Clinical Laboratory Improvement Act (CLIA), regulates all clinical human laboratory testing performed in the United States for the purposes of generating diagnostic or other health information. CLIA regulations address personnel qualifications, laboratory quality assurance standards, and documentation and validation of tests and procedures.[48] For laboratory tests themselves, CLIA categorizes tests based on the level of complexity into waived tests, moderate complexity, or high complexity. Genetic tests are considered high complexity, which indicates that a high degree of knowledge and skill is required to perform or interpret the test. Laboratories conducting high complexity tests must undergo proficiency testing at specified intervals, which consists of an external review of the laboratory's ability to accurately perform and interpret the test.[47,49] However, a specialty area specific for molecular and biologic genetic tests has yet to be established; therefore, specific proficiency testing of genetic testing laboratories is not required by CLIA.[47]

In regard to analytic validity, genetic tests fall into two primary categories; test kits and laboratory-developed tests (previously called home brews). Test kits are manufactured for use in laboratories performing the test and include all the reagents necessary to complete the analysis, instructions, performance outcomes, and details about which genetic variants can be detected. The U.S. Food and Drug Administration (FDA) regulates test kits as medical devices; however, despite more than 1,000 available genetic tests, there are fewer than ten FDA-approved test kits.[49] Laboratory-developed tests are performed in a laboratory that assembles its own testing materials in-house;[49] this category represents the most common form of genetic testing. Laboratory-developed tests are subject to the least amount of oversight, as neither CLIA nor the FDA evaluate the laboratories' proficiency in performing the test or clinical validity relative to the accuracy of the test to predict a clinical outcome.[47,49] The FDA does regulate manufactured analyte-specific reagents (ASRs) as medical devices. These small molecules are used to conduct laboratory-developed tests but can also be made by the laboratory. ASRs made in the laboratory are not subject to FDA oversight. For laboratory-developed tests utilizing manufactured commercially available ASRs, the FDA requires that the test be ordered by a health professional or other individual authorized to order the test by state law. However, this regulation does not distinguish between health providers caring for the patient or health providers who work for the laboratory offering the test.[49]

In addition to the regulation of classical clinical genetic tests is the regulatory oversight of research genetic testing. Laboratories performing genetic testing on a research basis are exempt from CLIA oversight if the laboratory does not report patient-specific results for the diagnosis, prevention, or treatment of any disease or impairment or the assessment of the health of individual patients.[47] However, there are anecdotal reports of research laboratories providing test results for clinical purposes with the caveat that the laboratory recommends that testing be repeated in a clinical CLIA-approved laboratory. In addition, there is no established mechanism that determines when a test has sufficient analytic and clinical validity to be offered clinically.[49] Currently, the decision to offer a genetic test clinically is at the discretion of the laboratory director.

Evidence regarding the implications of this narrow regulatory oversight of genetic tests is limited and consists predominantly of laboratory director responses to quality assurance surveys. A survey of 133 laboratory directors performing genetic tests found that 88% of laboratories employed one or more American Board of Medical Genetics (ABMG)-certified or ABMG-eligible professional geneticists, and 23% had an affiliation with at least one doctoral-prepared geneticist. Eight percent of laboratories did not employ and were not affiliated with doctoral-level genetics professionals. Laboratory-developed tests were performed in 70% of laboratories. Sixty-three percent of laboratories provided an interpretation of the test result as part of the test report.[50] Another survey of 190 laboratory directors found that 97% were CLIA-certified for high complexity testing. Sixteen percent of laboratories reported no specialty area certification; those without specialty certification represented laboratories with the most volume of tests performed and offered the most extensive test selection.[47] Of laboratories with specialty certification, not all had certification relevant to genetic tests, with 48% reporting pathology certification, 46% chemistry certification, and 41% clinical cytogenetics certification. Sixteen percent of directors reported participation in no formal external proficiency testing program, although 77% performed some informal proficiency testing when a formal external proficiency testing program was not available.

The most frequent reason cited for lack of proficiency testing participation was lack of available proficiency testing programs. Laboratory directors estimated that in the past 2 years 37% issued three or fewer incorrect reports, and 35% issued at least four incorrect reports. Analytic errors such as faulty reagent, equipment failure, or human error, increased 40% with each decrease in level of proficiency training completed.[47] An international genetic testing laboratory director survey involving 18 countries found that 64% of the 827 laboratories that responded accepted samples from outside their country.[51] Similar to the U.S. study, 74% reported participation in some form of proficiency testing. Fifty-three percent of the laboratories required a copy of the consent to perform the test, and 72% of laboratories retained specimens indefinitely that were submitted for testing.[51]

The U.S. Department of Health and Human Services Secretary’s Advisory Committee on Genetics, Health, and Society has published a detailed report regarding the adequacy and transparency of the current oversight system for genetic testing in the United States.[52] The Committee identified gaps in the following areas:

• Regulations governing clinical laboratory quality.
• Oversight of the clinical validity of genetic tests.
• The number and identification of laboratories performing genetic tests and the specific genetic tests being performed.
• Level of current knowledge about the clinical usefulness of genetic tests.
• Educational preparation in genetics of health providers, the public health community, patients, and consumers.

In October 2014, the FDA posted the notification regarding its plans to develop draft guidance on the regulation of laboratory-developed tests.[53] Draft guidance documents outlining the framework for regulatory oversight for the industry and clinical laboratories were published later in 2014 for public review and comment. Given the potential of such regulatory action to affect the wide spectrum of genetic tests in clinical practice, proposed draft guidelines have been discussed and reviewed by a number of professional associations, eliciting policy statements and analyses from various professional associations, including the American Society of Human Genetics (ASHG)Exit Disclaimer and the Association for Molecular PathologyExit Disclaimer. The issue of FDA oversight of laboratory-developed tests remains under consideration.