Large-scale integration of functional assay data for the resolution of germline BRCA1 and BRCA2 variants of uncertain significance.

Integration of functional assay data resolved 80.1% of BRCA1 VUSs and 69.5% of BRCA2 VUSs, classifying 6,517 missense variants in a large-scale study.

• Why it matters: Accurate classification of BRCA1 and BRCA2 variants is crucial for cancer risk assessment, but many variants remain uncertain, limiting clinical decision-making.
• What they did: The study curated, harmonized, and integrated functional data from 3,247 BRCA1 and 6,177 BRCA2 missense variants using ordinal categorical variables and ClinGen guidelines, combining results from multiple assays and case-control studies.
• The result: This approach confirmed that benign and pathogenic variants are associated with low and high breast cancer risk, enabling the classification of over 6,500 variants and improving variant interpretation accuracy.