Dominant-negative pathogenic variant BRIP1 c.1045G>C is a high-risk allele for non-mucinous epithelial ovarian cancer: A case-control study
Authors
Flaum, N.van Veen, E. M.
Smith, O.
Amico, S.
Newman, W. G.
Crosbie, Emma J
Edmondson, Richard
Smith, M. J.
Evans, D Gareth R
Affiliation
Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, ManchesteIssue Date
2021
Metadata
Show full item recordAbstract
BRIP1 is a moderate susceptibility epithelial ovarian cancer (EOC) gene. Having identified the BRIP1 c.1045G>C missense variant in a number of families with EOC, we aimed to investigate the frequency of this and BRIP1.2392C>T pathogenic variant in patients with breast cancer (BC) and/or EOC. A case-control study of 3767 cases and 2043 controls was undertaken investigating the presence of these variants using Sanger sequencing and gene panel data. Individuals with BC and/or EOC were grouped by family history. BRIP1 c.1045G>C was associated with increased risk of BC/EOC (OR = 37.7; 95% CI 5.3-444.2; P = 0.0001). The risk was highest for women with EOC (OR = 140.8; 95% CI 23.5-1723.0; P < 0.0001) and lower for BC (OR = 11.1; 95% CI 1.2-106.5; P = 0.1588). BRIP1 c.2392C>T was associated with smaller risks for BC/EOC (OR = 5.4; 95%CI 2.4-12.7; P = 0.0003), EOC (OR = 5.9; 95% CI 1.3-23.0; p = 0.0550) and BC (OR = 5.3; 95%CI 2.3-12.9; P = 0.0009). Our study highlights the importance of BRIP1 as an EOC susceptibility gene, especially in familial EOC. The variant BRIP1 c.1045G>C, rs149364097, is of particular interest as its dominant-negative effect may confer a higher risk of EOC than that of the previously reported BRIP1 c.2392C>T nonsense variant. Dominant-negative missense variants may confer higher risks than their loss-of-function counterparts.Citation
Flaum N, Veen EM, Smith O, Amico S, Newman WG, Crosbie EJ, et al. Dominant?negative pathogenic variant BRIP1 c. 1045G >C is a high?risk allele for non?mucinous epithelial ovarian cancer: A case?control study. Clinical Genetics. Wiley; 2021.Journal
Clinical GeneticsDOI
10.1111/cge.14068PubMed ID
34585738Additional Links
https://dx.doi.org/10.1111/cge.14068Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.1111/cge.14068