Dominant-negative pathogenic variant BRIP1 c.1045G>C is a high-risk allele for non-mucinous epithelial ovarian cancer: A case-control study
van Veen, E. M.
Newman, W. G.
Crosbie, Emma J
Smith, M. J.
Evans, D Gareth R
AffiliationDivision of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Mancheste
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AbstractBRIP1 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.
CitationFlaum 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.
- BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer.
- Authors: Weber-Lassalle N, Hauke J, Ramser J, Richters L, Groß E, Blümcke B, Gehrig A, Kahlert AK, Müller CR, Hackmann K, Honisch E, Weber-Lassalle K, Niederacher D, Borde J, Thiele H, Ernst C, Altmüller J, Neidhardt G, Nürnberg P, Klaschik K, Schroeder C, Platzer K, Volk AE, Wang-Gohrke S, Just W, Auber B, Kubisch C, Schmidt G, Horvath J, Wappenschmidt B, Engel C, Arnold N, Dworniczak B, Rhiem K, Meindl A, Schmutzler RK, Hahnen E
- Issue date: 2018 Jan 24
- Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer.
- Authors: Ramus SJ, Song H, Dicks E, Tyrer JP, Rosenthal AN, Intermaggio MP, Fraser L, Gentry-Maharaj A, Hayward J, Philpott S, Anderson C, Edlund CK, Conti D, Harrington P, Barrowdale D, Bowtell DD, Alsop K, Mitchell G, AOCS Study Group., Cicek MS, Cunningham JM, Fridley BL, Alsop J, Jimenez-Linan M, Poblete S, Lele S, Sucheston-Campbell L, Moysich KB, Sieh W, McGuire V, Lester J, Bogdanova N, Dürst M, Hillemanns P, Ovarian Cancer Association Consortium., Odunsi K, Whittemore AS, Karlan BY, Dörk T, Goode EL, Menon U, Jacobs IJ, Antoniou AC, Pharoah PD, Gayther SA
- Issue date: 2015 Nov
- Rare <i>BRIP1</i> Missense Alleles Confer Risk for Ovarian and Breast Cancer.
- Authors: Moyer CL, Ivanovich J, Gillespie JL, Doberstein R, Radke MR, Richardson ME, Kaufmann SH, Swisher EM, Goodfellow PJ
- Issue date: 2020 Feb 15
- Rare Germline Genetic Variants and the Risks of Epithelial Ovarian Cancer.
- Authors: Pavanello M, Chan IH, Ariff A, Pharoah PD, Gayther SA, Ramus SJ
- Issue date: 2020 Oct 19
- <i>BRIP1</i>, a Gene Potentially Implicated in Familial Colorectal Cancer Type X.
- Authors: Martín-Morales L, Garre P, Lorca V, Cazorla M, Llovet P, Bando I, García-Barberan V, González-Morales ML, Esteban-Jurado C, de la Hoya M, Castellví-Bel S, Caldés T
- Issue date: 2021 Feb