Journal: Nature communications
This study addresses how to classify BRCA2 variants of uncertain significance (VUS), focusing on the C‑terminal DNA binding domain where two prior saturation genome editing studies had already measured functional effects of all possible single-nucleotide variants.
- The authors combined the raw functional data from those two studies (covering 6,383 variants) into several composite models and tested each against variants with known clinical classifications.
- The best-performing approach, termed the “Integrated VarCall Model,” achieved 98.8% accuracy, outperforming each original dataset and other combined models.
- Applying this integrated functional model within the framework of ClinGen BRCA1/2 expert panel ACMG/AMP specifications, they were able to classify 5,926 BRCA2 variants (92.8%) in this region as either pathogenic (735 variants) or benign (5,191 variants).
This substantially reduces the number of VUS and has direct implications for more confident hereditary cancer risk assessment, counseling, and management in patients carrying BRCA2 variants in the C‑terminal DNA binding domain.