Dominant‐negative pathogenic variant
BRIP1
c.
1045G
>C is a high‐risk allele for non‐mucinous epithelial ovarian cancer: A case‐control study
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.
