Dominant‐negative pathogenic variant BRIP1 c.1045G>C is a high‐risk allele for non‐mucinous epithelial ovarian cancer: A case‐control study. Issue 1 (7th October 2021)

• Record Type: Journal Article
• 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
• Is Part Of: Clinical genetics. Volume 101:Issue 1(2022)
• Page Start: 48
• Page End: 54
• Publication Date: 2021-10-07
• Subjects: breast cancer -- BRIP1 -- epithelial ovarian cancer -- familial cancer predisposition -- genetics; Medical genetics -- Periodicals; 616.0420
• DOI: 10.1111/cge.14068
• Languages: English
• ISSNs: 0009-9163

Abstract

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 :