High-throughput functional evaluation of BRCA2 variants of unknown significance

Masachika Ikegami, Shinji Kohsaka (), Toshihide Ueno, Yukihide Momozawa, Satoshi Inoue, Kenji Tamura, Akihiko Shimomura, Noriko Hosoya, Hiroshi Kobayashi, Sakae Tanaka and Hiroyuki Mano ()
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Masachika Ikegami: National Cancer Center Research Institute
Shinji Kohsaka: National Cancer Center Research Institute
Toshihide Ueno: National Cancer Center Research Institute
Yukihide Momozawa: RIKEN Center for Integrative Medical Sciences
Satoshi Inoue: National Cancer Center Research Institute
Kenji Tamura: National Cancer Center Hospital
Akihiko Shimomura: National Cancer Center Hospital
Noriko Hosoya: The University of Tokyo
Hiroshi Kobayashi: The University of Tokyo
Sakae Tanaka: The University of Tokyo
Hiroyuki Mano: National Cancer Center Research Institute

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-16141-8

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