ArticleCancer research2023
Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C.
Article in Cancer research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers, 1 of them a synthesis that pooled it.
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Who cites it
10 citing papers in PubMed, 1 synthesis or guideline pooled it, 14 citations in OpenAlex.
- Management of individuals with heterozygous germline pathogenic variants in RAD51C, RAD51D, and BRIP1: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).Genetics in medicine : official journal of the American College of Medical Genetics · 2025Guideline
- RAD51C breast cancer-identified variants with attenuated homologous recombination function exhibit sensitivity to combined PARP1 and ATR inhibition.NAR cancer · 2026Article
- Tumor and germline testing with next generation sequencing in epithelial ovarian cancer: a prospective paired comparison using an 18-gene panel.Molecular oncology · 2026Article
- PIBF1 (p.R405Q) germline variant identified in cancer susceptibility family impairs protein stability and function.Cancer cell international · 2025Article
- Comprehensive RAD51C ovarian cancer variant analysis uncouples homologous recombination and replicative functions.Nature communications · 2025Article
- Genetic Features of Tumours Arising in the Context of Suspected Hereditary Cancer Syndromes withGenes · 2025Article
- Using AI-predicted protein structures as a reference to predict loss-of-function activity in tumor suppressor breast cancer genes.Computational and structural biotechnology journal · 2024Article
- Article
- The human Shu complex promotes RAD51 activity by modulating RPA dynamics on ssDNA.Nature communications · 2024Article
- Finding significance: New perspectives in variant classification of the RAD51 regulators, BRCA2 and beyond.DNA repair · 2023Review
Corrections and comments
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Authors and funding
44 authors at 15 institutions in 2 countries.
Funding
Abstract
Pathogenic protein-truncating variants of RAD51C, which plays an integral role in promoting DNA damage repair, increase the risk of breast and ovarian cancer. A large number of RAD51C missense variants of uncertain significance (VUS) have been identified, but the effects of the majority of these variants on RAD51C function and cancer predisposition have not been established. Here, analysis of 173 missense variants by a homology-directed repair (HDR) assay in reconstituted RAD51C-/- cells identified 30 nonfunctional (deleterious) variants, including 18 in a hotspot within the ATP-binding region. The deleterious variants conferred sensitivity to cisplatin and olaparib and disrupted formation of RAD51C/XRCC3 and RAD51B/RAD51C/RAD51D/XRCC2 complexes. Computational analysis indicated the deleterious variant effects were consistent with structural effects on ATP-binding to RAD51C. A subset of the variants displayed similar effects on RAD51C activity in reconstituted human RAD51C-depleted cancer cells. Case-control association studies of deleterious variants in women with breast and ovarian cancer and noncancer controls showed associations with moderate breast cancer risk [OR, 3.92; 95% confidence interval (95% CI), 2.18-7.59] and high ovarian cancer risk (OR, 14.8; 95% CI, 7.71-30.36), similar to protein-truncating variants. This functional data supports the clinical classification of inactivating RAD51C missense variants as pathogenic or likely pathogenic, which may improve the clinical management of variant carriers. SIGNIFICANCE: Functional analysis of the impact of a large number of missense variants on RAD51C function provides insight into RAD51C activity and information for classification of the cancer relevance of RAD51C variants.
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