AI Article Synopsis

  • * Current guidelines for assessing germline variants don't adequately incorporate data from tumors, which can be crucial for understanding their significance in cancer cases.
  • * The authors present an optimized protocol that utilizes somatic tumor profiling to better evaluate the pathogenicity of germline variants, including details about case selection and key supporting evidence like loss of heterozygosity (LOH).

Article Abstract

The interpretation of hereditary genetic sequencing variants is often limited due to the absence of functional data and other key evidence to assess the role of variants in disease. Cancer genetics is unique, as two sets of genomic information are often available from a cancer patient: somatic and germline. Despite the progress made in the integrated analysis of somatic and germline findings, the assessment of pathogenicity of germline variants in high penetrance genes remains grossly underutilized. Indeed, standard ACMG/AMP guidelines for interpreting germline sequence variants do not address the evidence derived from tumor data in cancer. Previously, we have demonstrated the utility of somatic tumor data as supporting evidence to elucidate the role of germline variants in patients suspected with VHL syndrome and other cancers. We have leveraged the key elements of cancer genetics in these cases: genes with expected high disease penetrance and those with a known biallelic mechanism of tumorigenicity. Here we provide our optimized protocol for evaluating the pathogenicity of germline variants using informative somatic profiling data. This protocol provides details of case selection, assessment of personal and family evidence, somatic tumor profiles, and loss of heterozygosity (LOH) as supporting evidence for the re-evaluation of germline variants.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9237939PMC
http://dx.doi.org/10.1016/j.mex.2022.101761DOI Listing

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