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Numerous nontruncating missense variants of the  BRCA2  gene have been identified, but there is a lack of convincing evidence, such as familial data, demonstrating their clinical relevance and they thus remain unactionable. To assess the pathogenicity of variants of unknown significance (VUSs) within  BRCA2 , here we develop a method, the MANO-B method, for high-throughput functional evaluation utilizing  BRCA2 -deficient cells and poly (ADP-ribose) polymerase (PARP) inhibitors. The estimated sensitivity and specificity of this assay compared to those of the International Agency for Research on Cancer classification system is 95% and 95% (95% confidence intervals: 77–100% and 82–99%), respectively. We classify the functional impact of 186  BRCA2  VUSs with our computational pipeline, resulting in the classification of 126 variants as normal/likely normal, 23 as intermediate, and 37 as abnormal/likely abnormal. We further describe a simplified, on-demand annotation system that could be used as a companion diagnostic for PARP inhibitors in patients with unknown  BRCA2  VUSs.

High-throughput functional evaluation of BRCA2 variants of unknown significance