RAD51D – Hereditary Breast and Ovarian Cancer Syndrome

RAD51D (HGNC:9823) encodes a paralog of RAD51 that is essential for homologous recombination (HR)–mediated DNA repair. Heterozygous germline pathogenic variants in RAD51D confer an increased risk of hereditary breast and ovarian cancer syndrome (HBOC) by impairing HR and sensitizing cells to cross-linking agents and PARP inhibitors.

Genetic evidence supporting an autosomal dominant mode of inheritance includes detection of RAD51D pathogenic variants in multiple large cohorts. In a case–control sequencing study of 5 131 HBOC index cases, RAD51D variants were associated with an odds ratio of 5.23 [1.46–13.17] for breast or ovarian cancer (PMID:29988077). In a Swedish clinical series of 4 622 women referred for HBOC testing, 13 (0.28%) carried RAD51D pathogenic variants and clinical action was altered accordingly (PMID:37563628).

Founder‐effect and recurrent alleles further strengthen the association. In a genetically unique French-Canadian cohort, RAD51D c.620C>T (p.Ser207Leu) was identified in 17.6% of HBOC families and 11.3% of early-onset ovarian cancer cases, with the highest carrier frequency of 3.4% in sporadic cases versus 0.1% in controls (PMID:35565380). Segregation of c.620C>T with disease was observed in at least 7 affected relatives in independent pedigrees (PMID:35565380).

The RAD51D variant spectrum includes loss-of-function alleles (e.g., c.694C>T (p.Arg232Ter)), splice‐site changes, frameshifts, and missense substitutions. The recurrent founder allele c.620C>T (p.Ser207Leu) is the most extensively characterized.

Functional studies demonstrate RAD51D haploinsufficiency and variant‐specific defects. RAD51D-deficient chicken DT40 cells exhibit impaired HR, chromosomal instability, and hypersensitivity to cross-linking agents (PMID:11283264). The p.Ser207Leu missense mutation disrupts RAD51D–XRCC2 interaction, abrogates HR, and confers PARP inhibitor sensitivity in human cells (PMID:28646019).

No convincing conflicting evidence has been reported. Together, genetic and experimental data support a Strong ClinGen clinical validity for RAD51D in HBOC. Clinically actionable testing of RAD51D identifies individuals eligible for enhanced surveillance, risk-reducing surgery, and PARP inhibitor therapy.

Key Take-home: Heterozygous RAD51D pathogenic variants cause HR deficiency and confer a strong predisposition to hereditary breast and ovarian cancer, informing precision prevention and therapy.

References

• Human molecular genetics • 2001 • Chromosome instability and defective recombinational repair in knockout mutants of the five Rad51 paralogs PMID:11283264
• Nucleic acids research • 2006 • Disparate requirements for the Walker A and B ATPase motifs of human RAD51D in homologous recombination PMID:16717288
• Genetics in medicine • 2018 • Landscape of pathogenic variations in a panel of 34 genes and cancer risk estimation from 5131 HBOC families PMID:29988077
• European journal of medical genetics • 2018 • Mutational analysis of RAD51C and RAD51D genes in hereditary breast and ovarian cancer families from Murcia (southeastern Spain) PMID:29409816
• Cancer research • 2017 • Functionally Null RAD51D Missense Mutation Associates Strongly with Ovarian Carcinoma PMID:28646019
• Cancers • 2022 • The Genetic and Molecular Analyses of RAD51C and RAD51D Identifies Rare Variants Implicated in Hereditary Ovarian Cancer from a Genetically Unique Population PMID:35565380
• BMC cancer • 2023 • Extended genetic analysis and tumor characteristics in over 4600 women with suspected hereditary breast and ovarian cancer PMID:37563628

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