Genetics of Breast and Gynecologic Cancers–Health Professional Version (PDQ®)

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Changes to This Summary (03/04/2016)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Executive Summary

Added this new section.

Penetrance of Inherited Susceptibility to Hereditary Breast and/or Gynecologic Cancers

Added this new section.

High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes

Added text to state that the lifetime risks of ovarian cancer are 5.2% inRAD51C mutation carriers, 5.8% in BRIP1 mutation carriers, and 12% inRAD51D mutation carriers; risk-reducing salpingo-oophorectomy (RRSO) may be considered for these patients upon completion of childbearing (cited Ramus et al. and Song et al. as references 122 and 123, respectively).

The Li-Fraumeni syndrome section was comprehensively reviewed and extensively revised.

Revised text to state that an updated set of operational criteria for the diagnosis of Cowden syndrome based on a systematic literature review has been suggested and is currently utilized in the National Comprehensive Cancer Network (NCCN) guidelines. Also added text to state that the American College of Medical Genetics and Genomics (ACMG) suggests that referral for genetics consultation be considered for individuals with a personal history of or a first-degree relative with 1) adult-onset Lhermitte-Duclos disease or 2) any three of the major or minor criteria that have been established for the diagnosis of Cowden syndrome; detailed recommendations, including diagnostic criteria for Cowden syndrome, can be found in the NCCN and ACMG guidelines.

Moderate-Penetrance Genes Associated With Breast and/or Gynecologic Cancer

This section was renamed from Low- and Moderate-Penetrance Genes Associated With Breast and/or Ovarian Cancer.

Revised text to state that genes such as CHEK2 and ATM are associated with a 20% or higher lifetime risk of breast cancer; similarly, genes such as RAD51C, RAD51D, and BRIP1 are associated with a 5% to 10% risk of ovarian cancer; many of these genes are now included on multi-gene panels, although the clinical actionability of these findings remains uncertain and under investigation.

Added text to state that in a case-control study of 3,236 women with ovarian cancer, BRIP1mutations were more frequently associated with ovarian cancer risk (cited Ramus et al. as reference 12).

Revised text to state that RAD51C mutations have also been reported in Australian, British, Finnish, and Spanish non-BRCA1/2 ovarian cancer–only and breast/ovarian cancer families, and in unselected ovarian cancer cases. Also revised text to state that in addition to RAD51Cmutation carriers, there are other RAD51 paralogs, including RAD51B, RAD51D, and RAD51L1, that may be associated with breast and/or ovarian cancer risk.

Added text to state that in a case-control study of 3,429 ovarian cancer patients, RAD51Cand RAD51D mutations were more commonly found in ovarian cancer cases than in controls (cited Song et al. as reference 76).

Revised text to state that among the conflicting data is substantial evidence for a modest association between germline mutations in RAD51C and breast cancer and ovarian cancer.

Added SMARCA4 as a new subsection.

Low-Penetrance Genes and Loci

Added this new section.

Clinical Management of BRCA Mutation Carriers

The Risk-reducing mastectomy subsection was comprehensively reviewed and extensively revised.

Added text about a cohort study of 822 BRCA1/BRCA2 mutation carriers conducted in the Netherlands which did not observe a reduced risk of breast cancer after RRSO (cited Heemskerk-Gerritsen et al. as reference 81); in a response, investigators from the U.S. studies analyzed their data using the assumptions of the Dutch study but still observed an inverse association with RRSO and breast cancer risk (cited Chai et al. as reference 82). Also added text about a retrospective cohort of 676 women in which carriers having an RRSO at the time of breast cancer diagnosis had a reduced risk of breast cancer–specific mortality (cited Metcalfe et al. as reference 83).

Added text to state that despite discordant findings regarding RRSO and breast cancer risk in the existing literature, aggregate data suggest that there is a benefit, although the magnitude of this benefit may not be fully understood. Further prospective studies are needed to confirm these findings.

Updated Robson et al. and American College of Surgeons as references 331 and 332, respectively.

Psychosocial Issues in Inherited Breast and Ovarian Cancer Syndromes

Revised text to state that emotional responses to a BRCA test result may not generalize to individuals who test without extensive pretest counseling; for example, individuals who are tested with population BRCA screening may not have a family history of cancer; although pretest genetic counseling is recommended, this is not always done when genetic testing is ordered by nongenetic providers (cited Armstrong et al. as reference 118) or directly through commercial companies.

Added Emotional outcomes of recently diagnosed individuals as a new subsection.

This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

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