Abstract
Determination of the clinical relevance of rare germline variants of uncertain significance (VUSs) in the BRCA2 cancer predisposition gene remains a challenge as a result of limited availability of data for use in classification models. However, laboratory-based functional data derived from validated functional assays of known sensitivity and specificity may influence the interpretation of VUSs. We evaluated 252 missense VUSs from the BRCA2 DNA-binding domain by using a homology-directed DNA repair (HDR) assay and identified 90 as non-functional and 162 as functional. The functional assay results were integrated with other available data sources into an ACMG/AMP rules-based classification framework used by a hereditary cancer testing laboratory. Of the 186 missense variants observed by the testing laboratory, 154 were classified as VUSs without functional data. However, after applying protein functional data, 86% (132/154) of the VUSs were reclassified as either likely pathogenic/pathogenic (39/132) or likely benign/benign (93/132), which impacted testing results for 1,900 individuals. These results indicate that validated functional assay data can have a substantial impact on VUS classification and associated clinical management for many individuals with inherited alterations in BRCA2.
Original language | English (US) |
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Pages (from-to) | 458-468 |
Number of pages | 11 |
Journal | American journal of human genetics |
Volume | 108 |
Issue number | 3 |
DOIs | |
State | Published - Mar 4 2021 |
Keywords
- ACMG/AMP
- BRCA2
- breast cancer
- functional assay
- predisposition gene
- variant of uncertain significance
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)