Functional characterization of BRCA1 variants of unknown significance using homologous recombination repair assays.

This study evaluated 16 BRCA1 variants of uncertain significance (VUS) identified in a hereditary cancer genetic counseling setting. Researchers used two homologous recombination (HR) repair assays to assess the variants’ impact on DNA repair function.

Key findings include:

• Five VUS were classified as pathogenic due to significantly impaired HR efficiency.
• Eleven VUS were deemed benign.
• Two pathogenic variants were located outside known BRCA1 functional domains.
• Four of the pathogenic variants showed increased sensitivity to ionizing radiation.
• Two pathogenic variants also displayed hypersensitivity to the PARP inhibitor olaparib, indicating potential therapeutic implications.

The authors emphasize that HR-based functional assays, combined with sensitivity testing, provide timely and clinically relevant data. This approach aids in the classification of BRCA1 VUS for genetic counseling and personalized treatment decisions.