full-text:
Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results

Hum Mutat. Author manuscript; available in PMC 2011 April 13.

Published in final edited form as:

Hum Mutat. 2008 November; 29(11): 1282–1291.

doi: 10.1002/humu.20880

PMCID: PMC3075918

NIHMSID: NIHMS78152

Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results

Sharon E. Plon,^1,*# Diana M. Eccles,^2,* Douglas Easton,³ William D. Foulkes,⁴ Maurizio Genuardi,⁵ Marc S. Greenblatt,⁶ Frans B.L. Hogervorst,⁷ Nicoline Hoogerbrugge,⁸ Amanda B. Spurdle,⁹ and Sean Tavtigian¹⁰, for the IARC Unclassified Genetic Variants Working Group^†

¹ Departments of Pediatrics and Molecular and Human Genetics, Baylor Cancer Genetics Clinic, Baylor College of Medicine, Houston, TX, USA

² School of Medicine, University of Southampton, Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK

³ Cancer Research UK Genetic Epidemiology Unit Department of Public Health and Primary Care University of Cambridge, Cambridge, UK

⁴ Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada

⁵ Medical Genetics Unit, Department of Clinical Pathophysiology, University of Florence, Florence, Italy and Fiorgen Foundation for Pharmacogenomics, Sesto Fiorentino, Italy

⁶ Department of Medicine and Vermont Cancer Center, University of Vermont College of Medicine, Burlington, VT, USA

⁷ DNA-diagnostic laboratory of the Family Cancer Clinic, Dept of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

⁸ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands

⁹ Genetics and Population Health Division, Queensland Institute of Medical Research, Brisbane, Australia

¹⁰ International Agency for Research on Cancer; Lyon 69372, France

^# Corresponding Author: Sharon E. Plon, MD, PhD, FACMG, MC3-3320; 6621 Fannin St., Houston, TX 77030, Email: splon@bcm.edu , 832-824-4251(office); 832-825-4276 (fax)

^*authors contributed equally to this work

^†The Working Group members are listed in the Appendix.

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Abstract

Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic testing may detect changes that are clearly pathogenic, clearly neutral or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based genetic testing, describe other standardized reporting systems used in oncology and propose a standardized classification system for application to sequence based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based genetic tests to predict cancer risk.

Keywords: IARC, variants, cancer genetics, classification, recommendations