- Title
- Integration of tumour sequencing and case–control data to assess pathogenicity of RAD51C missense variants in familial breast cancer
- Creator
- Lim, Belle W. X.; Li, Na; Rowley, Simone M.; Thompson, Ella R.; McInerny, Simone; Zethoven, Magnus; Scott, Rodney J.; Devereux, Lisa; Sloan, Erica K.; James, Paul A.; Campbell, Ian G.
- Relation
- n p j Breast Cancer Vol. 8, no. 10
- Publisher Link
- http://dx.doi.org/10.1038/s41523-021-00373-y
- Publisher
- Nature Publishing Group
- Resource Type
- journal article
- Date
- 2022
- Description
- While protein-truncating variants in RAD51C have been shown to predispose to triple-negative (TN) breast cancer (BC) and ovarian cancer, little is known about the pathogenicity of missense (MS) variants. The frequency of rare RAD51C MS variants was assessed in the BEACCON study of 5734 familial BC cases and 14,382 population controls, and findings were integrated with tumour sequencing data from 21 cases carrying a candidate variant. Collectively, a significant enrichment of rare MS variants was detected in cases (MAF < 0.001, OR 1.57, 95% CI 1.00–2.44, p = 0.05), particularly for variants with a REVEL score >0.5 (OR 3.95, 95% CI 1.40–12.01, p = 0.006). Sequencing of 21 tumours from 20 heterozygous and 1 homozygous carriers of nine candidate MS variants identified four cases with biallelic inactivation through loss of the wild-type allele, while six lost the variant allele and ten that remained heterozygous. Biallelic loss of the wild-type alleles corresponded strongly with ER- and TN breast tumours, high homologous recombination deficiency scores and mutational signature 3. Using this approach, the p.Gly264Ser variant, which was previously suspected to be pathogenic based on small case–control analyses and loss of activity in in vitro functional assays, was shown to be benign with similar prevalence in cases and controls and seven out of eight tumours showing no biallelic inactivation or characteristic mutational signature. Conversely, evaluation of case–control findings and tumour sequencing data identified p.Ile144Thr, p.Arg212His, p.Gln143Arg and p.Gly114Arg as variants warranting further investigation.
- Subject
- breast cancer; cancer genetics; pathogenicity; tumor; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1469596
- Identifier
- uon:48284
- Identifier
- ISSN:2374-4677
- Rights
- This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Language
- eng
- Full Text
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