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

      Flaum, Nicola; orcid: 0000-0001-8900-0645; email: nicola.flaum@manchester.ac.uk; van Veen, Elke M.; orcid: 0000-0001-8618-2332; Smith, Olivia; Amico, Stephanie; Newman, William G.; orcid: 0000-0002-6098-9995; Crosbie, Emma J.; Edmondson, Richard; Smith, Miriam J.; orcid: 0000-0002-3184-0817; Evans, D. Gareth (Blackwell Publishing Ltd, 2021-10-07)
      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.