RAD51D – hereditary breast carcinoma

RAD51D is implicated in DNA repair via homologous recombination and heterozygous loss-of-function or deleterious missense variants predispose to hereditary breast carcinoma. ClinGen classifies the RAD51D–hereditary breast carcinoma association as Moderate based on replicated case–control data, moderate variant prevalence, and supportive functional studies.

1 Assess Clinical Validity

Inheritance is autosomal dominant with high penetrance for breast carcinoma. Multiple independent cohorts totaling >8 000 breast cancer cases and >13 000 controls demonstrated a moderate increased risk (OR 2–4) for RAD51D pathogenic variants ([PMID:34606182]). No large pedigrees with extensive segregation have been reported, but case–control and multi-ethnic panel testing provide consistent support.

2 Summarise Genetic Evidence

Genetic evidence reaches a ClinGen Strong tier for variant–disease correlation: RAD51D pathogenic alleles were identified in unselected breast cancer patients (n = 8 067) versus controls (n = 13 129) conferring moderate risk (OR:2–4) ([PMID:34606182]). A recurrent missense allele c.620C>T (p.Ser207Leu) was observed across diverse ancestries. Total proband counts for c.620C>T exceed eight carriers in breast cancer cohorts. Variant spectrum includes both truncating alleles (nonsense, frameshift, splice) and hypomorphic missense mutations disrupting function. No founder effect has been established for breast cancer, although RAD51D c.620C>T is enriched in ovarian carcinoma cohorts.

3 Summarise Functional / Experimental Evidence

Functional studies across species demonstrate RAD51D’s essential role in homologous recombination. Knockout DT40 cells lacking RAD51D exhibit chromosome instability and hypersensitivity to DNA crosslinking agents ([PMID:11283264]). The missense variant p.Ser207Leu abrogates XRCC2 interaction and impairs repair, conferring PARP-inhibitor sensitivity in human cells ([PMID:28646019]). Splice-altering variants further confirm haploinsufficiency as a pathogenic mechanism.

4 Address Conflicting Evidence

No studies have refuted RAD51D’s role in breast carcinoma. Low carrier frequencies in some European cohorts reflect moderate penetrance rather than lack of association.

5 Integrate & Conclude

Taken together, genetic association studies and mechanistic assays support RAD51D as a moderate-penetrance breast cancer susceptibility gene. Additional segregation data and large pedigrees would bolster evidence but exceed current ClinGen scoring caps. Key take-home: RAD51D variant screening should be included in multigene panels for hereditary breast carcinoma to guide risk assessment and therapeutic decision-making.

References

• PLoS One • 2019 • Discoveries beyond BRCA1/2: Multigene testing in an Asian multi-ethnic cohort suspected of hereditary breast cancer syndrome in the real world. PMID:30875412
• Cancer biology & medicine • 2021 • Association between 15 known or potential breast cancer susceptibility genes and breast cancer risks in Chinese women. PMID:34606182
• Molecular and cellular biology • 2001 • Chromosome instability and defective recombinational repair in knockout mutants of the five Rad51 paralogs. PMID:11283264
• Cancer research • 2017 • Functionally Null RAD51D Missense Mutation Associates Strongly with Ovarian Carcinoma. PMID:28646019

Evidence Based Scoring (AI generated)