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FANCE
FA complementation group E
FANCE is located on the short (p) arm of chromosome 6, at band 6p21.31. Arm ratio per GRCh38 - banding schematic.
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Overview
FANCE is located on chromosome 6 and belongs to a family of genes responsible for the Fanconi anaemia DNA repair pathway. This pathway safeguards genomic integrity by coordinating the cellular response to DNA interstrand crosslinks, lesions that covalently link both strands of the DNA double helix and block essential processes such as replication and transcription.
Pathogenic variants in FANCE follow an autosomal recessive inheritance pattern, meaning individuals require two altered copies to develop clinical features. The gene is included in multiple NHS Genomic Medicine Service panels covering cancer predisposition, bone marrow failure, and congenital anomalies, reflecting the spectrum of clinical presentations associated with Fanconi anaemia.
What the gene does
The FANCE protein serves as a core component of the FA core complex, a nuclear assembly comprising at least eight proteins that collaborate to detect and repair DNA interstrand crosslinks. When cells encounter such damage, the core complex coordinates the monoubiquitination of the FANCD2-FANCI heterodimer, a crucial modification that recruits downstream repair factors to the site of injury.
FANCE acts as a molecular scaffold within this complex, physically bridging other FA proteins and enabling the assembly of a functional repair machine. Through interactions with FANCC and other core components, FANCE ensures the complex localises correctly to chromatin and maintains stability under conditions of replicative stress. Without functional FANCE, cells accumulate unrepaired DNA damage, triggering cell cycle arrest, chromosomal breaks, and elevated rates of cell death.
This repair pathway is particularly important in rapidly dividing tissues, such as haematopoietic stem cells in bone marrow. Loss of FANCE function therefore has profound consequences for tissue maintenance and long-term genomic stability.
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Chromosome location
FANCE resides at chromosomal band 6p21.31 on the short arm of chromosome 6. This region of the genome is gene-dense and contains other medically important loci. The gene spans approximately 18 kilobases of genomic DNA and comprises 10 exons that encode a mature transcript.
Protein structure
The FANCE protein extends across 536 amino acids and contains several functionally important regions. A defined interaction domain spanning amino acids 150 to 371 mediates binding to FANCC, a critical partner in the FA core complex. This extended region enables stable association with the complex and contributes to its overall structural integrity.
A disordered region occupies amino acids 171 to 252 within the protein sequence. Intrinsically disordered regions are common in scaffold proteins and provide flexibility that allows multiple binding partners to engage with the same polypeptide chain, facilitating dynamic protein-protein interactions central to DNA repair coordination.
Key variants
Pathogenic variants in FANCE are distributed across the coding sequence, with loss-of-function alterations including nonsense mutations, frameshift deletions, and splice-site changes. These variants typically abolish protein expression or produce truncated products unable to participate in core complex assembly. Missense variants affecting the FANCC-interaction domain can also disrupt function by preventing stable incorporation into the repair machinery.
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.1041G>A | p.Trp347Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia complementation group E |
c.1222C>T | p.Gln408Ter | Pathogenic | ★★☆☆ | Fanconi anemia complementation group E |
c.1237+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia complementation group E |
c.1239dup | p.Pro414fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia complementation group E |
c.334del | p.Ser112fs | Pathogenic | ★★☆☆ | Fanconi anemia complementation group E |
c.339del | p.Leu114fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.350_351del | p.Val117fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia complementation group E |
c.538del | p.Ser180fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia complementation group E |
c.635del | p.Glu212fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia complementation group E |
c.769_772dup | p.Ala258fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia complementation group E |
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 FANCE cause Fanconi anaemia complementation group E, a rare autosomal recessive disorder. Affected individuals typically present in childhood with progressive bone marrow failure, leading to cytopenias and increased susceptibility to infections and bleeding. Developmental anomalies may include short stature, radial ray defects, microcephaly, and pigmentary skin changes, although clinical features vary considerably even among individuals with identical variants. The underlying genomic instability confers a substantially elevated risk of haematological malignancies, particularly acute myeloid leukaemia, as well as solid tumours in early adulthood.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic FANCE 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
FANCE holds green (high confidence) status across 18 NHS Genomic Medicine Service gene panels, reflecting robust evidence for clinical validity. These include panels for confirmed Fanconi anaemia or Bloom syndrome, cytopenias and congenital anaemias, and multiple cancer susceptibility panels covering childhood solid tumours, haematological malignancies, adult solid tumours, and head and neck cancer. The gene also appears on developmental panels addressing foetal anomalies, radial dysplasia, severe microcephaly, limb disorders, and monogenic short stature, underscoring the multisystem nature of Fanconi anaemia presentations.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does it mean if I carry one FANCE variant?
Carriers of a single pathogenic FANCE variant typically have no health effects themselves, as one working copy is generally sufficient for normal DNA repair. Carrier status becomes relevant for family planning, particularly if a reproductive partner is also a carrier, as each child would have a one-in-four chance of inheriting two altered copies and developing Fanconi anaemia.
How is Fanconi anaemia managed?
Management is coordinated by specialist centres and may include supportive care for bone marrow failure, surveillance for malignancies, and consideration of haematopoietic stem cell transplantation. Individuals with Fanconi anaemia also require careful monitoring for solid tumours and may benefit from modified treatment protocols if cancer develops, as they have heightened sensitivity to certain chemotherapy agents.
Are FANCE variants common in any population?
Pathogenic FANCE variants are rare across all populations studied. Fanconi anaemia as a whole has an estimated carrier frequency of approximately one in 300 in the general population, though FANCE accounts for only a small proportion of cases compared to more commonly affected genes such as FANCA.