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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
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
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
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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.
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Date
2021
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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.