Article

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: 5.05). 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, Jul 28, 2015
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    • "Relevant to this topic, the International Society for Gastrointestinal Hereditary Tumours (InSIGHT) has recently described the procedure undertaken to validate integrated methods for classifying mismatch repair gene variants in order to use them in a clinical context for Lynch syndrome (Thompson et al., 2013). The authors underlined the need of an international support to standardize also the development of databases in which the final VUS classification should be provided (Plon et al., 2008; Thompson et al., 2013). "
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    Human Mutation 07/2014; 35(7). DOI:10.1002/humu.22550 · 5.05 Impact Factor
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    • "CMGS and VKGL (2007) and the American Board of Medical Genetics (Zhang and Wang 2012). Other examples for variant classification include the five class categorisation protocol developed for BRCA1/2 gene variants, where Class 1 variants are " not pathogenic or of no clinical significance " , Class 3 variants are " uncertain " and Class 5 variants are " definitely pathogenic " (Plon et al. 2008). Each class of variants has different consequences for clinical management. "
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    Human Mutation 04/2014; 35(4). DOI:10.1002/humu.22525 · 5.05 Impact Factor
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    • "(MLH1) NM_000179.2 (MSH6), and NM_000535.5 (PMS2), and classified using a five class system (1 = neutral, 2 = likely neutral, 3 = uncertain , 4 = likely pathogenic, and 5 = pathogenic) (Plon et al. 2008; Spurdle 2010 "
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