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


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 at and then mutations were classified according to the five-class system IARC system recommended by the International Agency for Research on Cancer (IARC)[5]. "
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    ABSTRACT: Background: Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, caused by germline mutations in MisMatch Repair (MMR) genes, particularly in MLH1, MSH2 and MSH6. Patients with LS seem to have a more favourable prognosis than those with sporadic CRC, although the prognostic impact of different mutation types is unknown.Aim of our study is to compare survival outcomes of different types of MMR mutations in patients with LS-related CRC. Methods: 302 CRC patients were prospectively selected on the basis of Amsterdam or Revised Bethesda criteria to undergo genetic testing: direct sequencing of DNA and MLPA were used to examine the entire MLH1, MSH2 and MSH6 coding sequence.Patients were classified as mutation-positive or negative according to the genetic testing result. Results: A deleterious MMR mutation was found in 38/302 patients. Median overall survival (OS) was significantly higher in mutation-positive vs mutation-negative patients (102.6 vs 77.7 months, HR:0.63, 95%CI:0.46-0.89, p = 0.0083). Different types of mutation were significantly related with OS: missense or splicing-site mutations were associated with better OS compared with rearrangement, frameshift or non-sense mutations (132.5 vs 82.5 months, HR:0.46, 95%CI:0.16-0.82, p = 0.0153). Conclusions: Our study confirms improved OS for LS-patients compared with mutation-negative CRC patients. In addition, not all mutations could be considered equal: the better prognosis in CRC patients with MMR pathogenic missense or splicing site mutation could be due to different functional activity of the encoded MMR protein. This matter should be investigated by use of functional assays in the future.
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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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    ABSTRACT: Human genome sequencing is routine and will soon be a staple in research and clinical genetics. However, the promise of sequencing is often just that, with genome data routinely failing to reveal useful insights about disease in general or a person's health in particular. Nowhere is this chasm between promise and progress more evident than in the designation, "variant of uncertain significance" (VUS). Although it serves an important role, careful consideration of VUS reveals it to be a nebulous description of genomic information and its relationship to disease, symptomatic of our inability to make even crude quantitative assertions about the disease risks conferred by many genetic variants. In this perspective, I discuss the challenge of "variant interpretation" and the value of comparative and functional genomic information in meeting that challenge. Although already essential, genomic annotations will become even more important as our analytical focus widens beyond coding exons. Combined with more genotype and phenotype data, they will help facilitate more quantitative and insightful assessments of the contributions of genetic variants to disease.
    Preview · Article · Oct 2015 · Genome Research
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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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