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FANCB
FA complementation group B
FANCB is located on the short (p) arm of chromosome X, at band Xp22.2. Arm ratio per GRCh38 - banding schematic.
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Overview
FANCB encodes FA complementation group B protein, a key component of the Fanconi anaemia DNA repair pathway. This pathway removes DNA interstrand crosslinks that would otherwise block replication and transcription, threatening genomic stability. The gene is located on the X chromosome, making FANCB the only X-linked member of the Fanconi anaemia gene family. Pathogenic changes in FANCB lead to impaired DNA repair, resulting in bone marrow failure, developmental abnormalities, and markedly increased susceptibility to cancers including leukaemia and solid tumours. Because the gene follows X-linked inheritance, affected individuals are typically male, whilst female carriers may show mild or variable features.
What the gene does
The FANCB protein serves as a structural component of the Fanconi anaemia core complex, which also includes proteins encoded by FANCA, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM. This multi-protein assembly recognises sites of DNA damage, particularly interstrand crosslinks caused by environmental toxins or metabolic byproducts, and coordinates the recruitment of downstream repair factors. When DNA crosslinks are detected, the core complex monoubiquitinates FANCD2 and FANCI proteins, marking chromatin for repair. FANCB acts as an adaptor within the core complex, helping to stabilise interactions between other components and ensuring the assembly localises correctly to damaged DNA. Without functional FANCB, the entire pathway becomes disrupted, preventing cells from efficiently removing crosslinks. This leads to the accumulation of DNA breaks, chromosomal instability, and eventual cell death, particularly affecting rapidly dividing haematopoietic stem cells in the bone marrow.
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Chromosome location
FANCB is located on the short arm of the X chromosome at position Xp22.2. The gene spans approximately 40 kilobases of genomic DNA and contains 10 exons that encode a messenger RNA transcript of roughly 3 kilobases. Being positioned on the X chromosome distinguishes FANCB from all other Fanconi anaemia genes, which reside on autosomes, and accounts for the X-linked recessive inheritance pattern observed in affected families.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The FANCB protein comprises 859 amino acids with a predicted molecular weight of approximately 95 kilodaltons. Structural studies suggest the protein contains regions that mediate protein-protein interactions necessary for core complex assembly, though precise domain boundaries remain under investigation.
Key variants
Pathogenic variants in FANCB include nonsense mutations, frameshifts, and deletions that disrupt protein function. Because the gene follows X-linked inheritance, hemizygous males carrying a single pathogenic variant typically develop Fanconi anaemia, whilst heterozygous females are usually asymptomatic carriers. Some female carriers may exhibit skewed X-inactivation patterns leading to mild clinical features. Variant classification relies on evidence of functional impairment in DNA repair assays and segregation data from affected families.
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.781C>T | p.Arg261Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.851del | p.Pro284fs | Pathogenic/Likely pathogenic | ★★☆☆ | FANCB-related disorder |
g.(?_14861689)_(14891184_?)del | - | Pathogenic | ★☆☆☆ | Fanconi anemia |
g.(?_14875974)_(14891184_?)del | - | Pathogenic | ★☆☆☆ | Fanconi anemia |
c.101del | p.Asp34fs | Pathogenic | ★☆☆☆ | not provided |
c.1159_1162dup | p.Tyr388fs | Pathogenic | ★☆☆☆ | Fanconi anemia |
c.1437G>A | p.Trp479Ter | Pathogenic | ★☆☆☆ | Fanconi anemia |
c.1668del | p.Asp557fs | Pathogenic | ★☆☆☆ | Fanconi anemia complementation group B |
c.195dup | p.Thr66fs | Pathogenic | ★☆☆☆ | Fanconi anemia complementation group B |
c.455_458del | p.Phe152fs | 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
Pathogenic variants in FANCB cause Fanconi anaemia complementation group B, characterised by progressive bone marrow failure typically presenting in childhood, congenital abnormalities affecting the skeleton and other organ systems, and substantially elevated lifetime risk of cancers including acute myeloid leukaemia, myelodysplastic syndrome, and squamous cell carcinomas. Physical features may include radial ray abnormalities, short stature, microcephaly, skin pigmentation changes, and developmental anomalies affecting the heart, kidneys, or gastrointestinal tract. The severity and combination of features vary considerably between affected individuals. Because FANCB is X-linked, most diagnosed patients are male, though female carriers with highly skewed X-inactivation may occasionally present with clinical features.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic FANCB variants typically follow x-linked inheritance.
X-linked recessive: sons of a carrier mother have a 50% chance of being affected. Daughters have a 50% chance of being carriers.
UK clinical status
FANCB is classified as a green gene on multiple NHS Genomic Medicine Service gene panels, reflecting strong evidence for its role in inherited cancer predisposition and related conditions. It appears on the Adult solid tumours cancer susceptibility panel, Haematological malignancies cancer susceptibility panel, and Childhood solid tumours panel, recognising its role in cancer predisposition across age groups. FANCB is also included on the Confirmed Fanconi anaemia or Bloom syndrome panel, Cytopenias and congenital anaemias panel, and panels addressing specific developmental features such as Radial dysplasia, Severe microcephaly, and VACTERL-like phenotypes. This broad panel representation reflects the multi-system nature of Fanconi anaemia and supports genomic testing for individuals presenting with bone marrow failure, characteristic physical anomalies, or family histories of early-onset cancer.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
Why is FANCB inheritance different from other Fanconi anaemia genes?
FANCB is the only Fanconi anaemia gene located on the X chromosome, whilst all other FA genes are found on autosomes. This means FANCB follows X-linked recessive inheritance, primarily affecting males, whereas other FA genes follow autosomal recessive patterns affecting both sexes equally.
Can female carriers of FANCB variants develop symptoms?
Most female carriers remain asymptomatic, but those with highly skewed X-inactivation may develop mild to moderate features of Fanconi anaemia. The severity depends on which X chromosome is preferentially active in haematopoietic and other tissues.
What cancers are associated with FANCB variants?
Individuals with pathogenic FANCB variants face substantially elevated risk of acute myeloid leukaemia, myelodysplastic syndrome, and squamous cell carcinomas affecting the head, neck, and oesophagus. Cancer surveillance protocols are typically recommended for affected individuals and may be considered for some female carriers.