RAD51C – RAD51C-related Hereditary Breast and Ovarian Cancer Syndrome

RAD51C has been established as a breast and ovarian cancer predisposition gene through multiple independent studies. In an early large screen of hereditary breast and ovarian cancer (HBOC) families, two truncating RAD51C mutations were identified in 2 of 335 families with both breast and ovarian cancer and none in 1,053 breast-only families (PMID:21990120). Subsequent case–control analysis estimated an odds ratio of 4.54 for pathogenic RAD51C variants in HBOC (PMID:29988077).

A recurrent splicing founder variant, c.571+4A>G, was found in five Newfoundland HBOC probands, segregating on a shared 5.07 Mbp haplotype and causing exon 3 skipping with premature termination (PMID:31782267). In a French multicenter cohort of 4,630 BRCA1/2-negative patients, RAD51C pathogenic or likely pathogenic variants were detected in 36 individuals (7 % of non-BRCA P/LP variants) (PMID:37444530). RAD51C PVs also accounted for 0.54 % of cases in a Swedish clinical panel of 4,622 HBOC patients (PMID:37563628).

RAD51C acts in an autosomal dominant manner, with heterozygous loss-of-function predisposing to cancer. Segregation of c.571+4A>G in five affected family members supports pathogenicity. Across cohorts, at least 38 distinct P/LP variants—including frameshift, nonsense, splice-site, and missense changes—have been reported in HBOC patients.

Functional studies of RAD51C demonstrate a clear mechanism of haploinsufficiency. RAD51C-deficient chicken B-cell lines exhibit impaired homologous recombination (HR), spontaneous chromosome aberrations, sensitivity to cross-linking agents, and reduced RAD51 focus formation (PMID:11283264). Minigene splicing assays confirm that c.705G>T (p.Lys235Asn) and other intronic variants provoke exon skipping and premature truncation (PMID:35740625). Structural and biochemical analyses reveal that RAD51C interacts with XRCC3 and other RAD51 paralogs via ATP-binding interfaces essential for HR (PMID:36099300).

Replication fork protection and restart roles of the RAD51C–XRCC3 complex have been elucidated by CRISPR-engineered human cells and single-molecule assays, linking specific paralog interfaces to genomic stability and cancer predisposition (PMID:37488098). In functional complementation assays, the c.394A>C (p.Thr132Pro) missense variant abolishes ssDNA binding and confers chemosensitivity, underscoring clinical relevance (PMID:33832919).

Given the definitive genetic and moderate experimental evidence, RAD51C meets criteria for inclusion in HBOC diagnostic panels. Identification of RAD51C PVs informs risk-reducing strategies, genetic counseling, and eligibility for PARP inhibitor therapy. Continued functional characterization of novel RAD51C variants will refine clinical interpretation.

References

• Hum Mutat • 2012 • Analysis of RAD51C germline mutations in high-risk breast and ovarian cancer families and ovarian cancer patients PMID:21990120
• Am J Hum Genet • 2018 • Landscape of pathogenic variations in a panel of 34 genes and cancer risk estimation from 5131 HBOC families PMID:29988077
• Mol Genet Genomic Med • 2020 • A dominant RAD51C pathogenic splicing variant predisposes to breast and ovarian cancer in the Newfoundland population due to founder effect PMID:31782267
• Cancers • 2023 • Overview of the Genetic Causes of Hereditary Breast and Ovarian Cancer Syndrome in a Large French Patient Cohort. PMID:37444530
• Mol Cell Biol • 2001 • Chromosome instability and defective recombinational repair in knockout mutants of the five Rad51 paralogs PMID:11283264
• Cancers • 2022 • Minigene Splicing Assays Identify 20 Spliceogenic Variants of the Breast/Ovarian Cancer Susceptibility Gene RAD51C. PMID:35740625
• Proc Natl Acad Sci U S A • 2022 • Homologous recombination-deficient mutation cluster in tumor suppressor RAD51C identified by comprehensive analysis of cancer variants. PMID:36099300
• Nat Commun • 2023 • RAD51C-XRCC3 structure and cancer patient mutations define DNA replication roles. PMID:37488098
• Cold Spring Harb Mol Case Stud • 2021 • Long-term survival of an ovarian cancer patient harboring a RAD51C missense mutation. PMID:33832919

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