FAN1 – Hereditary Nonpolyposis Colon Cancer

Germline mutations in FAN1 have been implicated in hereditary nonpolyposis colon cancer (HNPCC), linking this Fanconi anemia–related nuclease to colorectal cancer predisposition. Initial exome sequencing of 3 affected individuals from a single pedigree meeting Amsterdam criteria revealed each carried a heterozygous nonsense variant in FAN1, despite mismatch repair–proficient tumors ([PMID:26052075]). Subsequent screening of 176 additional HNPCC families identified FAN1 mutations in approximately 3% of cases lacking known MMR gene defects ([PMID:26052075]).

Inheritance follows an autosomal dominant pattern, with the prototypical variant c.2128C>T (p.Arg710Ter) segregating in 3 affected relatives within the index family ([PMID:26052075]). Across the expanded cohort, at least five unrelated probands also harbored heterozygous FAN1 LoF alleles, confirming reproducible genetic evidence of risk ([PMID:26052075]).

The variant spectrum in HNPCC is dominated by premature termination alleles; c.2128C>T (p.Arg710Ter) was the first and most recurrent LoF event reported. No missense or splice‐site variants with equivalent penetrance have yet been described in this context.

Functional assays of FAN1 mutants demonstrate impaired interstrand crosslink repair and reduced nuclease activity in vitro, consistent with a loss‐of‐function mechanism that compromises genome integrity ([PMID:26052075]). No rescue experiments or animal models specific to colorectal carcinogenesis have been reported to date.

The convergence of genetic segregation and functional impairment supports a Moderate level of genetic evidence and Limited functional evidence under ClinGen criteria. No conflicting studies disputing the association with HNPCC have been published.

Key Take-home: Heterozygous truncating variants in FAN1 confer autosomal dominant risk for hereditary nonpolyposis colon cancer and warrant inclusion in diagnostic gene panels for colorectal cancer predisposition.

References

• Gastroenterology • 2015 • Germline Mutations in FAN1 Cause Hereditary Colorectal Cancer by Impairing DNA Repair. PMID:26052075

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