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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, Nicola
van Veen, Elke M.
Smith, Olivia
Amico, Stephanie
Newman, William G.
Crosbie, Emma J.
Edmondson, Richard
Smith, Miriam J.
Evans, D. Gareth
Source :
Clinical Genetics; Jan2022, Vol. 101 Issue 1, p48-54, 7p
Publication Year :
2022

Abstract

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00099163
Volume :
101
Issue :
1
Database :
Complementary Index
Journal :
Clinical Genetics
Publication Type :
Academic Journal
Accession number :
153993319
Full Text :
https://doi.org/10.1111/cge.14068