FANCC – Fanconi anemia complementation group C

Fanconi anemia complementation group C (FA-C) is an autosomal recessive disorder characterized by congenital anomalies, bone marrow failure and cancer susceptibility. Biallelic variants in FANCC cause 14% of Fanconi anemia cases (PMID:8639804). Clinical onset varies from early childhood to adolescence, reflecting allelic heterogeneity and modifier effects.

Genetic evidence for FANCC in FA-C includes at least 8 unrelated probands with biallelic loss-of-function or splice variants detected by comprehensive mutation screening (PMID:17924555). Two founder mutations predominate: the exon 4 donor splice mutation c.456+4A>T and the exon 1 frameshift (delG322) together accounting for ~90% of known FANCC alleles (PMID:8639804). Multiple additional truncating variants (nonsense, frameshift, canonical splice) have been reported in diverse populations.

The variant spectrum comprises missense, short insertions/deletions, splice-site mutations and deep intronic alleles. The recurrent intronic mutation c.456+4A>T has been observed in Ashkenazi Jewish FA-C patients and leads to exon skipping (PMID:8639804). Other pathogenic alleles include c.5dup (p.Gln3fs) and c.117del (p.Gln40fs) among many novel truncating changes identified in cohort studies.

Functional assays in patient-derived lymphoblasts demonstrate that FANCC deficiency results in hypersensitivity to DNA-crosslinking agents and defective monoubiquitination of FANCD2. Overexpression of the amino-terminal truncated isoform FRP-50 partially rescues mitomycin C sensitivity, linking genotype to cellular phenotype (PMID:8639804). Complementation studies confirmed the pathogenicity of 1806insA and R548X while identifying D195V as a benign polymorphism (PMID:8882868).

Protein–protein interaction analyses reveal that FANCC binds FANCA to form a nuclear complex required for chromosomal stability; the patient-derived L554P mutation abrogates this binding and nuclear localization (PMID:9398857). In Fancc–/– mice, impaired Jak/STAT signaling and defective CD4+ T cell differentiation mirror the immunological defects seen in FA-C patients (PMID:15356134).

Studies of heterozygous FANCC carriers reveal no significant increase in cancer prevalence across three generations, confirming a strictly recessive inheritance and low carrier cancer risk (PMID:18210922).

Integration of genetic and experimental data supports a Moderate overall ClinGen clinical validity for FANCC-FA-C based on multiple unrelated probands, strong functional concordance and well-characterized founder alleles. Genetic evidence is Strong (biallelic LoF variants in ≥8 probands), and functional evidence is Moderate (robust cell and animal model data). FANCC testing provides diagnostic confirmation in FA-C, informs carrier screening in high-risk populations and underpins future gene-targeted therapies.

References

• Blood • 1996 • Clinical variability of Fanconi anemia (type C) results from expression of an amino terminal truncated Fanconi anemia complementation group C polypeptide with partial activity PMID:8639804
• Human genetics • 1996 • Sequence variations in the Fanconi anaemia gene, FAC: pathogenicity of 1806insA and R548X and recognition of D195V as a polymorphic variant PMID:8882868
• Nature genetics • 1997 • The Fanconi anaemia proteins, FAA and FAC, interact to form a nuclear complex PMID:9398857
• Journal of immunology • 2004 • Impaired type I IFN-induced Jak/STAT signaling in FA-C cells and abnormal CD4+ Th cell subsets in Fancc-/- mice PMID:15356134
• The Israel Medical Association journal: IMAJ • 2007 • Prevalence of breast and colorectal cancer in Ashkenazi Jewish carriers of Fanconi anemia and Bloom syndrome PMID:18210922
• Human mutation • 2008 • Genetic subtyping of Fanconi anemia by comprehensive mutation screening PMID:17924555

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