Purpose: The identification of variants of uncertain significance and genetic data from variant carriers in a rules-based variant (VUS) in the BRCA1 and BRCA2 genes by hereditary cancer testing classification model for BRCA2. poses great challenges for the clinical management of variant Results: Of 133 missense variants, 44 were designated as non-carriers. The ACMG/AMP (American College of Medical Genetics functional and 89 were designated as functional in the HDR assay. and Genomics/Association for Molecular Pathology) variant clasWhen combined with genetic and clinical information from a single sification framework, which incorporates multiple sources of evidiagnostic laboratory in an ACMG/AMP-variant classification dence, has the potential to establish the clinical relevance of many framework, 66 variants previously classified by the diagnostic VUS. We sought to classify the clinical relevance of 133 single-laboratory were correctly classified, and 62 of 67 VUS (92.5%) were nucleotide substitution variants encoding missense variants in the reclassified as likely pathogenic (n ¼ 22) or likely benign (n ¼ 40). In DNA-binding domain (DBD) of BRCA2 by incorporating results total, 44 variants were classified as pathogenic/likely pathogenic, 84 from a validated functional assay into an ACMG/AMP-variant as benign/likely benign, and 5 remained as VUS. classification model from a hereditary cancer–testing laboratory. Conclusions: Incorporation of HDR functional analysis into an Experimental Design: The 133 selected VUS were evaluated ACMG/AMP framework model substantially improves BRCA2 using a validated homology-directed double-strand DNA break VUS re-classification and provides an important tool for determinrepair (HDR) functional assay. Results were combined with clinical ing the clinical relevance of individual BRCA2 VUS.
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