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

作者：Sharon E. Plon, Diana M. Eccles, Douglas F. Easton, William D. Foulkes, Maurizio Genuardi, Marc S. Greenblatt, Frans B.L. Hogervorst, Nicoline Hoogerbrugge, Amanda B. Spurdle, Sean V. Tavtigian, for the IARC Unclassified Genetic Variants Working Group · 发表于：Human Mutation · 年份：2008 · DOI：10.1002/humu.20880 · 被引用次数：928 · 研究领域：BRCA gene mutations in cancer、Genetic factors in colorectal cancer、Genomics and Rare Diseases

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 synd...