Sharon E. Plon and Diana M. Eccles contributed equally to this work.
Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results†
Article first published online: 24 OCT 2008
© 2008 Wiley-Liss, Inc.
Special Issue: Special Issue: Assessing Mutation Pathogenicity in Cancer Susceptibility Genes
Volume 29, Issue 11, pages 1282–1291, November 2008
How to Cite
Plon, S. E., Eccles, D. M., Easton, D., Foulkes, W. D., Genuardi, M., Greenblatt, M. S., Hogervorst, F. B.L., Hoogerbrugge, N., Spurdle, A. B. and Tavtigian, S. V. (2008), Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum. Mutat., 29: 1282–1291. doi: 10.1002/humu.20880
For the Mutation Pathogenicity Special Issue
The members of the Working Group are listed in the Appendix.
- Issue published online: 24 OCT 2008
- Article first published online: 24 OCT 2008
- Manuscript Accepted: 21 JUL 2008
- Manuscript Received: 22 MAY 2008
- Australian National Health Medical Research Council
- Canadian Breast Cancer Research Alliance
- Ente Cassa di Risparmio Firenze
- Lake Champlain Cancer Research Organization
- National Institutes of Health (NIH). Grant Numbers: HG004064, CA 96536, CA116167
- cancer genetics;
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. Hum Mutat 29(11), 1282–1291, 2008. © 2008 Wiley-Liss, Inc.