RAD51C – Fanconi anemia complementation group O

RAD51C is a member of the RAD51 paralog family essential for homologous recombination (HR) and maintaining genome stability. Biallelic functional alterations in RAD51C define the Fanconi anemia complementation group O (FANCO), manifesting as defective repair of DNA interstrand crosslinks and chromosomal instability. No unrelated human probands with pathogenic RAD51C variants causing FANCO have been reported in the supplied evidence, and familial segregation data are lacking, supporting a Limited genetic evidence classification.

Experimental studies demonstrate that loss of RAD51C severely impairs HR. RAD51C-deficient DT40 chicken B-lymphocyte cell lines exhibit spontaneous chromosomal aberrations, heightened sensitivity to mitomycin C and cisplatin, and defective RAD51 focus formation, all rescued by human RAD51 overexpression (PMID:11283264). Moreover, RAD51C splice variants lacking exons 6–8 are overexpressed in colorectal tumors, correlate with promoter methylation, altered FANCD2 focus formation, and suggest a mechanistic link to FA pathway dysfunction (PMID:25669972).

Integration of these findings supports that RAD51C haploinsufficiency or loss-of-function disrupts the FA pathway and HR, leading to FANCO. However, the absence of documented biallelic variants in unrelated patients and segregation data confines the association to Limited clinical validity. Additional well-characterized biallelic probands and segregation studies would strengthen the evidence base. Key take-home: RAD51C is a clinically actionable FA-O gene, where biallelic loss-of-function impairs HR and may guide diagnostic testing for unexplained FA phenotypes.

References

• Oncotarget • 2015 • Overexpression of Rad51C splice variants in colorectal tumors. PMID:25669972
• Molecular and cellular biology • 2001 • Chromosome instability and defective recombinational repair in knockout mutants of the five Rad51 paralogs. PMID:11283264

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