RAD51C – RAD51C-related Hereditary Breast Carcinoma

RAD51C is an established moderate-penetrance predisposition gene for autosomal dominant hereditary breast carcinoma. Germline loss-of-function (LoF) and splice-site variants in RAD51C are significantly enriched in breast cancer cohorts, particularly in estrogen receptor–negative and triple-negative subtypes, supporting clinical genetic testing and targeted therapies.

Clinical Validity

The overall gene-disease association is classified as Strong based on identification of approximately 30 unrelated probands with RAD51C LoF variants across multiple studies, including case-control evidence with high odds ratios, and segregation of a recurrent splice-site founder variant showing loss of heterozygosity in tumors. These data meet ClinGen criteria for a strong clinical validity classification.

Genetic Evidence

RAD51C predisposition to breast carcinoma follows an autosomal dominant inheritance pattern. In a large study of 3 080 BRCA1/2-negative breast cancer cases versus 4 840 controls, germline LoF variants (including c.394dup (p.Thr132fs)) were detected in 0.4% of cases versus 0.04% of controls (odds ratio 8.67) (PMID:30949688). A recurrent splice-site variant, c.571+4A>G, segregated in five Newfoundland families with hereditary breast and ovarian cancer, shared a 5.07 Mbp haplotype, and demonstrated tumor loss of the wild-type allele (PMID:31782267). Across multigene panel screenings, RAD51C mutation prevalence ranges from 0.3% to 0.4%, justifying its inclusion in diagnostic panels.

Variant Spectrum

Reported pathogenic RAD51C variants include small insertions and deletions leading to frameshifts (e.g., c.394dup (p.Thr132fs)), essential splice-site alterations (e.g., c.905-2A>C), and missense changes disrupting protein function or splicing. Founder and recurrent alleles have been documented, underscoring population-specific testing strategies.

Functional Evidence

Functional studies consistently demonstrate that RAD51C deficiency impairs homologous recombination (HR). RAD51C knockout in DT40 cells yields chromosome instability, mitomycin C hypersensitivity, and reduced Rad51 focus formation (PMID:11283264). Structural analysis of the RAD51C-XRCC3 complex revealed ATP-binding interfaces essential for DNA replication fork protection and restart, defining separable replication stress response roles that correlate with patient variant phenotypes (PMID:37488098).

Integration and Clinical Utility

Integrating genetic and experimental data establishes RAD51C as a clinically actionable breast cancer susceptibility gene. Identification of RAD51C LoF and splice-site variants informs risk assessment, guides predictive testing of relatives, and may predict tumor sensitivity to DNA-damaging agents and PARP inhibitors. Ongoing large-scale sequencing efforts and functional assays will further refine variant classification.

Key Take-home: Germline RAD51C loss-of-function and splice-site variants confer a strong risk for hereditary breast carcinoma, supporting their inclusion in diagnostic panels and informing precision management.

References

• Journal of the National Cancer Institute | 2019 | Combined Tumor Sequencing and Case-Control Analyses of RAD51C in Breast Cancer PMID:30949688
• Molecular genetics & genomic medicine | 2020 | A dominant RAD51C pathogenic splicing variant predisposes to breast and ovarian cancer in the Newfoundland population due to founder effect PMID:31782267
• Molecular and cellular biology | 2001 | Chromosome instability and defective recombinational repair in knockout mutants of the five Rad51 paralogs PMID:11283264
• Nature Communications | 2023 | RAD51C-XRCC3 structure and cancer patient mutations define DNA replication roles PMID:37488098

Evidence Based Scoring (AI generated)