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FANCF
FA complementation group F
FANCF is located on the short (p) arm of chromosome 11, at band 11p14.3. Arm ratio per GRCh38 - banding schematic.
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Overview
FANCF is located on chromosome 11 and produces a 374-amino-acid protein that forms part of the Fanconi anaemia core complex [PMID:17529967]. This complex recognises DNA interstrand crosslinks and coordinates their repair. Inherited pathogenic variants in FANCF lead to Fanconi anaemia complementation group F, a rare autosomal recessive disorder. Affected individuals typically present with progressive bone marrow failure, congenital anomalies such as skeletal and renal malformations, and markedly elevated risk of haematological malignancies and solid tumours [PMID:26151332]. The gene appears on multiple NHS Genomic Medicine Service panels, including those for cancer susceptibility and developmental disorders.
What the gene does
Within the FA core complex, FANCF acts as a structural component that helps other proteins assemble correctly [PMID:17529967]. When the cell detects DNA damage, this multi-protein machinery relocates to the injury site and initiates a cascade of chemical modifications that recruit repair enzymes. FANCF itself does not cut or modify DNA directly; instead, it maintains the structural integrity of the complex and supports proper recognition of damaged sites. Without functional FANCF, cells cannot efficiently tag downstream repair proteins, leaving DNA crosslinks unresolved. These persistent lesions cause replication machinery to stall and chromosomes to break, which drives the bone marrow failure and cancer predisposition characteristic of Fanconi anaemia [PMID:26151332]. Laboratory tests demonstrate that cells lacking FANCF show heightened vulnerability to agents that create DNA crosslinks.
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Chromosome location
FANCF resides at chromosomal band 11p14.3 on the short arm of chromosome 11. The gene spans a relatively compact genomic region and encodes a single primary transcript. Structural features of the locus have not been extensively mapped in public databases, though the gene's position places it within a region that harbours several other genes involved in cellular growth and differentiation.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. Bioinformatic analyses suggest that FANCF lacks classical catalytic motifs or well-defined structural domains annotated in major protein databases. The protein appears to function primarily through protein-protein interaction surfaces that mediate its role as a structural scaffold within the FA core complex.
Key variants
Pathogenic variants in FANCF are distributed across the coding sequence and include nonsense mutations, frameshifts, and splice-site changes that result in loss of functional protein [PMID:28158555]. Most affected individuals carry two loss-of-function alleles, consistent with autosomal recessive inheritance. Founder mutations have been identified in specific populations, and carrier frequencies vary by ancestry. Variant interpretation follows international guidelines, with pathogenic classifications reserved for changes demonstrably disrupting DNA repair function.
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.133_136del | p.His45fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.219del | p.Arg74fs | Pathogenic | ★★☆☆ | Fanconi anemia complementation group F |
c.24_25insA | p.Asp9fs | Pathogenic | ★★☆☆ | Fanconi anemia |
c.267_268del | p.Cys89_Asp90delinsTer | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.388dup | p.Gln130fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.538del | p.Ala180fs | Pathogenic | ★★☆☆ | Fanconi anemia |
c.604del | p.Phe201_Leu202insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.658G>T | p.Glu220Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.698_699del | p.Gly233fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia complementation group F |
c.84del | p.Ala29fs | Pathogenic | ★★☆☆ | Fanconi anemia complementation group F |
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
Biallelic pathogenic variants in FANCF cause Fanconi anaemia complementation group F, characterised by congenital anomalies, progressive bone marrow failure, and heightened cancer risk. Clinical features typically emerge in childhood and may include short stature, radial ray defects, skin pigmentation changes, and renal or cardiac malformations. Haematological complications include thrombocytopenia, anaemia, and progression to myelodysplastic syndrome or acute myeloid leukaemia. Individuals with Fanconi anaemia also face substantially elevated risk of solid tumours, particularly squamous cell carcinomas of the head, neck, and anogenital regions. Management involves haematopoietic stem cell transplantation for bone marrow failure and ongoing surveillance for malignancy.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic FANCF 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
FANCF is included on multiple NHS Genomic Medicine Service PanelApp panels with green (high-evidence) classification. These include Adult Solid Tumours Cancer Susceptibility, Childhood Solid Tumours Cancer Susceptibility, Confirmed Fanconi Anaemia or Bloom Syndrome, Haematological Malignancies Cancer Susceptibility, and panels addressing developmental anomalies such as Radial Dysplasia, Severe Microcephaly, and Fetal Anomalies. Green status indicates robust evidence supporting clinical use of FANCF testing in relevant diagnostic pathways. Carrier screening for FANCF may be considered in families with known pathogenic variants or in populations with elevated carrier frequencies.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is Fanconi anaemia?
Fanconi anaemia is an inherited disorder caused by pathogenic variants in genes responsible for DNA crosslink repair, including FANCF. It typically presents with bone marrow failure, developmental abnormalities, and increased cancer risk, particularly leukaemia and squamous cell carcinomas.
How is FANCF inherited?
FANCF follows an autosomal recessive inheritance pattern. An individual must inherit a pathogenic variant from both parents to develop Fanconi anaemia. Carriers with one pathogenic variant generally do not show symptoms but can pass the variant to their children.
Why is FANCF included on UK cancer susceptibility panels?
Individuals with biallelic FANCF pathogenic variants face markedly elevated risk of haematological malignancies and solid tumours. Early identification allows for tailored surveillance and management strategies, including haematopoietic stem cell transplantation and cancer screening protocols.