Reinterpretation of Conflicting ClinVar BRCA1 Missense Variants Using VarSome and CanVIG-UK Gene-Specific Guidance

Background: The accurate interpretation of the BRCA1/2 variant is critical for diagnosing and treating hereditary breast and ovarian cancers. ClinVar is a widely used public database for genetic variants. Conflicting classifications of pathogenicity can occur when different submitters categorize the same genetic variant inconsistently as pathogenic (PV), likely pathogenic (LPV), likely benign (LBV), benign (BV), or a variant of uncertain significance (VUS). The conflicting ClinVar BRCA1/2 variant classifications hinder clinical decision making. We reinterpreted 450 BRCA1 missense variants with conflicting interpretations in ClinVar (accessed on 20 December 2022). Methods: VarSome and the BRCA1/BRCA2: CanVIG-UK gene-specific guidance (CanVIG-UK) classifications were compared, and the five original classifications were consolidated into three categories (PV/LPV, VUS, and BV/LBV). Consensus analysis was performed between re-extracted ClinVar data and VarSome and CanVIG-UK results. Results: The three-category classification of the variants resulted in an overall concordance rate of 58.9% for BRCA1 missense variant interpretation between CanVIG-UK and VarSome, with VarSome having rates of 11.3, 24.7, and 64.0% for PV/LPV, VUS, and BV/LBV classifications and CanVIG-UK having rates of 11.1, 51.6, and 37.3% for P/LPV, VUS, and BV/LBV classifications, respectively. No variants classified as PV/LPV in VarSome were classified as BV/LBV in CanVIG-UK and vice versa. By 1 May 2024, 3.8% (17/450) of these conflicting variants reached a consensus classification in ClinVar and were definitively classified (9 PV/LPV, 1 VUS, and 7 BV/LBV). Conclusions: VarSome and CanVIG-UK have different features that help improve the accuracy of pathogenicity classification, highlighting the potential complementary use of both tools to support clinical decision making.