Abstract
Editorial summaryAdvances in genetic analysis have revealed new complexities in the interpretation of genetic variants. Correct assessment of a genetic variant relies on the clinical context and knowledge of the underlying biology. We outline four scenarios encountered in genetic testing where careful consideration of the origin of genetic variation is required for variant interpretation.
Highlights
Advances in genetic analysis have revealed new complexities in the interpretation of genetic variants
In addition to mutations associated with cancer, low-frequency somatic mutations associated with local tissue proliferations and vascular malformations typical of mosaic overgrowth syndromes have recently been discovered
Classic assumptions about inherited variants associated with cancer predisposition have recently been challenged; these assumptions include the need for multiple affected generations, mutations in specific genes being related to a specific spectrum of cancers, or that variants detected in peripheral blood reflect only the germline
Summary
Advances in genetic analysis have revealed new complexities in the interpretation of genetic variants. Extensive genomic analyses of a large number of patients with varying phenotypes have exposed a complex relationship between pathogenic variants identified in the context of inherited and acquired conditions. We describe four key areas where there is interplay between germline and somatic genetic mutations that need be considered in relationship to an observed phenotype for the correct variant interpretation in a clinical context. The four areas we will address are: 1) germline pathogenic variants discovered as part of tumor-based testing, 2) tumor-based testing performed for the purpose of clarifying germline mutation status, 3) somatic mutations detected in peripheral blood as part of cancer predisposition testing, and 4) mosaic mutations detected in somatic overgrowth syndromes (Fig. 1). Current guidelines for interpretation of inherited genetic variants, such as from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, do not adequately address clinical context or somatic biological phenomena in the classification schema. These findings highlight that one must consider the possibility of a germline origin for pathogenic variants when evaluating cancer tissue, even in the absence of a family history
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