RAD50 – Hereditary Breast Carcinoma

Germline RAD50 variants have been identified in familial and population-based cohorts of hereditary breast carcinoma, with 15 probands carrying truncating or missense alleles across multiple studies ([PMID:28241424], [PMID:16385572], [PMID:16474176], [PMID:19190165], [PMID:34606182]). There is minimal segregation evidence (n=2 affected relatives) and conflicting case-control results: a Finnish founder LoF allele (c.687del (p.Ser229ArgfsTer6)) showed an OR of 4.3 in Northern Finns but was absent in French and Chinese cohorts. Overall, the clinical validity is classified as Limited given the small number of segregations and inconsistent replication across populations.

Functional assays support a haploinsufficiency mechanism: RAD50 truncating mutations yield reduced protein expression, impaired MRN complex function, and increased genomic instability in lymphoblastoid and breast cancer cells, consistent with a modest predisposition model. Conversely, several case-control and screening studies failed to confirm risk associations in non-Finnish cohorts, introducing disputed evidence. Additional large‐scale, segregated family studies are needed to clarify risk penetrance. Key Take-home: RAD50 germline alleles may confer low‐penetrance breast cancer risk in specific populations but currently lack sufficient familial and reproducible evidence for clinical implementation.

References

• International journal of molecular sciences • 2017 • Exome Sequencing in a Family with Luminal-Type Breast Cancer Underpinned by Variation in the Methylation Pathway. [PMID:28241424]
• International journal of cancer • 2006 • Evaluation of RAD50 in familial breast cancer predisposition. [PMID:16385572]
• Carcinogenesis • 2006 • RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability. [PMID:16474176]
• Cancer epidemiology, biomarkers & prevention • 2009 • Rad50 c.687delT does not contribute significantly to familial breast cancer in a French population. [PMID:19190165]
• Cancer biology & medicine • 2021 • Association between 15 known or potential breast cancer susceptibility genes and breast cancer risks in Chinese women. [PMID:34606182]
  

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