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FANCC
FA complementation group C
FANCC encodes a protein that forms part of the Fanconi anaemia core complex, critical for repairing DNA damage and maintaining genomic stability. The FANCC gene provides instructions for making a protein component of the Fanconi anaemia pathway, a cellular system that responds to DNA damage during replication.
FANCC is located on the long (q) arm of chromosome 9, at band 9q22.32. Arm ratio per GRCh38 - banding schematic.
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Overview
FANCC (FA complementation group C) is located on chromosome 9 at band 9q22.32 and encodes a 558-amino-acid protein integral to the Fanconi anaemia DNA repair pathway. This pathway becomes active when DNA replication encounters interstrand cross-links, aberrant bonds between bases on opposing strands that prevent the replication machinery from progressing. Such cross-links can arise from endogenous metabolic by-products or exposure to certain chemotherapy agents. Pathogenic variants in FANCC are inherited in an autosomal recessive pattern and account for approximately 15 percent of all Fanconi anaemia cases, a condition characterised by bone marrow failure, congenital anomalies, and predisposition to cancer. The gene is recognised on multiple NHS Genomic Medicine Service panels, reflecting its clinical importance in hereditary cancer susceptibility and haematological disorders.
What the gene does
The FANCC protein serves as one of eight FA proteins that assemble into the FA core complex, alongside two Fanconi anaemia-associated proteins. This multi-subunit complex functions as a molecular checkpoint during DNA replication, detecting stalled replication forks caused by interstrand cross-links. Once activated, the FA core complex catalyses the monoubiquitination of two downstream effector proteins, FANCD2 and FANCI, through covalent addition of individual ubiquitin molecules. This post-translational modification acts as a signal that recruits specialised DNA repair enzymes to the site of damage, enabling the cross-link to be excised and the DNA strands to be restored.
Without functional FANCC protein, the FA core complex cannot form properly or carry out its ubiquitination activity. Consequently, cells harbouring FANCC variants accumulate unrepaired DNA cross-links, leading to replication fork collapse, chromosome breaks, and genomic instability. This defect manifests clinically as progressive bone marrow failure, increased sensitivity to DNA cross-linking agents, and elevated cancer risk, particularly myeloid leukaemias and solid tumours in early adulthood.
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Chromosome location
FANCC is situated on the long arm of chromosome 9 at cytogenetic band 9q22.32. The gene spans multiple exons encoding a transcript that produces a 558-amino-acid protein. This chromosomal region has been associated with several genomic rearrangements and deletions in individuals with Fanconi anaemia, though the majority of pathogenic variants are point mutations or small insertions and deletions rather than large structural changes.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The FANCC polypeptide, comprising 558 amino acids and catalogued in UniProt as Q00597, lacks the well-defined catalytic or DNA-binding motifs found in some other FA pathway members. Current evidence suggests its primary contribution is structural or regulatory within the FA core complex. Protein interaction studies indicate that FANCC mediates contacts with other core complex subunits, stabilising the assembly and enabling the complex to localise correctly to chromatin during DNA damage responses. The absence of discrete functional domains underscores the protein's role as a scaffold component rather than an enzymatic player in the repair machinery.
Key variants
Pathogenic variants in FANCC are distributed throughout the coding sequence, with most leading to premature termination of translation or disruption of critical protein-protein interaction surfaces. Many of these variants result in absent or severely reduced levels of FANCC protein, preventing FA core complex assembly. Missense variants that permit protein expression but impair function have also been reported, typically affecting residues important for interactions with other FA core components or for complex stability.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.124C>T | p.Gln42Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.125dup | p.Glu43fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.129_142del | p.Glu43fs | Pathogenic | ★★☆☆ | Fanconi anemia |
c.169del | p.Ser57fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.227G>A | p.Trp76Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.265dup | p.Ile89fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.276G>A | p.Trp92Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.293_296del | p.Ile98fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.294_297del | p.Asn99fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.45G>A | p.Trp15Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in FANCC are responsible for Fanconi anaemia, an autosomal recessive disorder characterised by progressive bone marrow failure, congenital abnormalities, and markedly increased cancer susceptibility. Affected individuals typically present in childhood with cytopenias, and many exhibit physical features such as short stature, radial ray defects, skin pigmentation changes, and microcephaly. The spectrum of haematological malignancies includes acute myeloid leukaemia and myelodysplastic syndrome, whilst solid tumours, particularly of the head and neck, emerge with higher frequency in early adulthood. Clinical presentation can be variable, and some individuals with milder variants may present later in life.
Inheritance pattern
Conditions caused by pathogenic FANCC variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
FANCC holds green classification status on numerous NHS Genomic Medicine Service gene panels, reflecting strong evidence for its clinical validity. These include the Confirmed Fanconi anaemia or Bloom syndrome panel (R229), Adult solid tumours cancer susceptibility, Childhood solid tumours cancer susceptibility, Haematological malignancies cancer susceptibility, and Cytopenias and congenital anaemias panels. Additional memberships span panels for Radial dysplasia, Severe microcephaly (R88), Fetal anomalies (R21), Monogenic short stature (R453), and Pigmentary skin disorders (R236), underscoring the broad phenotypic spectrum associated with FANCC variants. This extensive panel representation supports clinical genomic testing for individuals with features suggestive of Fanconi anaemia or unexplained familial cancer syndromes involving haematological or solid tumours.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the difference between FANCC and other Fanconi anaemia genes?
FANCC is one of multiple genes that cause Fanconi anaemia when both copies carry pathogenic variants. Each FA gene encodes a different protein in the DNA repair pathway, and variants in FANCC account for roughly 15 percent of all Fanconi anaemia cases. The clinical features are generally similar across FA complementation groups, though severity and specific congenital anomalies can vary.
How is FANCC-related Fanconi anaemia inherited?
Fanconi anaemia caused by FANCC variants follows an autosomal recessive inheritance pattern. This means an individual must inherit a pathogenic variant from both parents to develop the condition. Carriers, who have one pathogenic variant, typically do not show symptoms but can pass the variant to their children.
Are FANCC variants associated with cancer risk in carriers?
Current evidence focuses primarily on individuals with two pathogenic FANCC variants, who have substantially elevated cancer risk. Research into whether single-copy carriers face modestly increased cancer susceptibility is ongoing, but no strong consensus has emerged to support routine cancer surveillance for heterozygous carriers alone.
References
- Kitao H, Takata M. Fanconi anemia: a disorder defective in the DNA damage response. International journal of hematology. 2011. PMID: 21331524
- Deakyne JS, Mazin AV. Fanconi anemia: at the crossroads of DNA repair. Biochemistry. Biokhimiia. 2011. PMID: 21568838
- Kee Y, D'Andrea AD. Expanded roles of the Fanconi anemia pathway in preserving genomic stability. Genes & development. 2010. PMID: 20713514
- de Winter JP, Joenje H. The genetic and molecular basis of Fanconi anemia. Mutation research. 2009. PMID: 19061902
- Taniguchi T, D'Andrea AD. Molecular pathogenesis of Fanconi anemia: recent progress. Blood. 2006. PMID: 16493006
- Mathew CG. Fanconi anaemia genes and susceptibility to cancer. Oncogene. 2006. PMID: 16998502