FANCC – Colorectal Cancer

Heterozygous loss‐of‐function variants in the Fanconi anemia complementation group C gene, FANCC, have been implicated in germline predisposition to colorectal cancer. In a cohort of 74 familial colorectal cancer (CRC) patients from 40 unrelated Spanish families, whole‐exome sequencing revealed enrichment for rare, heterozygous FANCC variants in 6 families, including a frameshift allele c.595dup (p.Leu199fs) (PMID:27165003).

Inheritance is consistent with autosomal dominant CRC predisposition, as carriers of FANCC loss‐of‐-function alleles showed strong family aggregation but no mutations in known high‐penetrance CRC genes. Six probands harbored FANCC variants, of which one carried the recurrent LoF frameshift c.595dup (p.Leu199fs) (PMID:27165003). No formal segregation counts were reported.

Functionally, FANCC encodes a core component of the Fanconi anemia DNA damage repair pathway, which is essential for interstrand crosslink repair and maintenance of genomic stability. Haploinsufficiency of FANCC may compromise DNA repair capacity, promoting colorectal carcinogenesis in heterozygous carriers.

To date, evidence is limited to a single‐center exome study without independent replication or detailed segregation analysis. No additional case–control series or functional assays specific to CRC predisposition have been reported.

Overall, current data support a Limited clinical validity for FANCC in CRC predisposition based on enrichment of LoF alleles in familial cases. Further replication in independent cohorts and comprehensive co‐segregation studies are required to establish a definitive association.

Key Take‐home: FANCC heterozygous loss‐of‐function variants should be considered in the genetic workup of unexplained familial colorectal cancer.

References

• European journal of human genetics • 2016 • The Fanconi anemia DNA damage repair pathway in the spotlight for germline predisposition to colorectal cancer. PMID:27165003

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