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Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women

Journal article published in 2016 by Timothy R. (Timothy) Rebbeck, Tara M. Friebel, T. M. Friebel, Tm Friebel, Nandita Mitra, Fei Wan, Stephanie Chen, M. O. W. (Mark ) Friebel, Irene L. (Irene) Andrulis, Paraskevi Apostolou, Norbert Arnold, Banu K. (Banu) Arun, Daniel Barrowdale, Javier Benitez, Raanan Berger and other authors.
This paper is available in a repository.
This paper is available in a repository.

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Abstract

Background: Most $\textit{BRCA1}$ or $\textit{BRCA2}$ mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both $\textit{BRCA1}$ and $\textit{BRCA2}$ are rare, and the consequences of transheterozygosity are poorly understood. Methods: From 32,295 female $\textit{BRCA1/2}$ mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at $\textit{BRCA1}$ (SH1) or $\textit{BRCA2}$ (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. Results: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; $p$ = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 ($p$ = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 ($p$ = 0.231), but was on average 4.5 years younger in TH than in SH2 ($p$