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IARC Unclassified Genetic Variants Working Group: Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results

Department of Pediatrics, Baylor Cancer Genetics Clinic, Baylor College of Medicine, Houston, Texas, USA.
Human Mutation (Impact Factor: 5.14). 11/2008; 29(11):1282-91. DOI: 10.1002/humu.20880
Source: PubMed

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.

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Available from: Sharon E Plon
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    • "Interpretation of identified mutations' pathogenic significance was performed searching each variant in the InSiGHT (available athttp://www.insight-group.org) and then mutations were classified according to the five-class system IARC system recommended by the International Agency for Research on Cancer (IARC)[5]. www.impactjournals.com/oncotarget "
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    • "Both descriptions are efforts to say something yet respect the principle that it is better to draw a crude and imprecise, but not incorrect, conclusion than to be elegantly and precisely wrong. Indeed, it is hardly novel to suggest that quantitation is a valuable goal in this context (Plon et al. 2008). Given interpretive and data limitations , perhaps " VUS, " like democracy, is simply the worst choice except for all the other possible options. "
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    • "In their work, the authors benchmarked the reliability of in silico predictions comparing their results with experimental assays and demonstrating that bioinformatics tools can be used for pathogenicity prediction of uncertain variants. For each VUS, the posterior odds ratio (OR) for pathogenicity was calculated as detailed in Methods and a final classification following the rules suggested by Plon et al. [52] compiled. For the PHD family, 42 VUS were classified as pathogenic (Class 5; Table 1), 36 VUS as likely pathogenic (Class 4; Table 2) and 30 VUS remain uncertain (Class 3; Table 3 "
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