TY - JOUR
T1 - High-throughput functional evaluation of BRCA2 variants of unknown significance
AU - Ikegami, Masachika
AU - Kohsaka, Shinji
AU - Ueno, Toshihide
AU - Momozawa, Yukihide
AU - Inoue, Satoshi
AU - Tamura, Kenji
AU - Shimomura, Akihiko
AU - Hosoya, Noriko
AU - Kobayashi, Hiroshi
AU - Tanaka, Sakae
AU - Mano, Hiroyuki
N1 - Funding Information:
The authors thank A. Maruyama for technical assistance and N. Tanabe and T. Yoshida for collecting data. This study was supported by the World-leading Innovative Graduate Study Program for Life Science and Technology, The University of Tokyo, as part of the WISE Program (Doctoral Program for World-leading Innovative & Smart Education), MEXT, Japan; JSPS KAKENHI grants (#19J13207); grants from the Program for Integrated Database of Clinical and Genomic Information under Grant Number JP18kk0205003, the Leading Advanced Projects for Medical Innovation (LEAP) under Grant Number JP18am0001001, and the Practical Research for Innovative Cancer Control under Grant Number JP18ck0106252 from the Japan Agency for Medical Research and Development, AMED; a grant for Endowed Department (Department of Medical Genomics, Graduate School of Medicine, The University of Tokyo) from Eisai Co., Ltd.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85085158909&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85085158909&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-16141-8
DO - 10.1038/s41467-020-16141-8
M3 - Article
C2 - 32444794
AN - SCOPUS:85085158909
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2573
ER -
