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FANCM
FA complementation group M
FANCM is located on the long (q) arm of chromosome 14, at band 14q21.2. Arm ratio per GRCh38 - banding schematic.
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Overview
FANCM (FA complementation group M) encodes a large protein involved in the cellular response to DNA damage, particularly crosslinks that block replication and transcription. The gene is located on chromosome 14 and produces a 2,048 amino acid protein that functions as both a DNA translocase and a scaffolding platform for assembling repair complexes. Although originally identified through its association with Fanconi anaemia when paired with certain biallelic mutations, FANCM variants are now recognised for their broader implications in cancer predisposition and reproductive health. The protein's ability to recognise stalled replication forks and coordinate appropriate repair pathways makes it a critical guardian of genomic stability across diverse tissues.
What the gene does
The FANCM protein functions primarily as a DNA translocase, using energy from ATP hydrolysis to move along DNA strands and remodel structures that arise during replication stress. Its helicase ATP-binding domain and DEAH box motif enable it to recognise aberrant DNA structures, including stalled replication forks and interstrand crosslinks. Once bound to damaged DNA, FANCM acts as a landing platform, recruiting the FA core complex and other repair factors to the lesion site. The protein coordinates the initial steps of the Fanconi anaemia pathway, which ultimately leads to the monoubiquitination of downstream effectors that execute DNA repair. Beyond its role in crosslink repair, FANCM participates in homologous recombination by promoting fork regression and preventing inappropriate recombination events that could destabilise the genome. Through its interaction domains, FANCM bridges multiple repair pathways, integrating signals about DNA damage with decisions about cell cycle progression and repair strategy selection.
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Chromosome location
FANCM is located on the long arm of chromosome 14 at position 21.2 (14q21.2). The gene spans a substantial genomic region and contains multiple exons that encode the 2,048 amino acid protein. This chromosomal location places FANCM within a region that has been studied for its association with various genomic rearrangements, though the gene itself maintains a relatively stable structure across human populations.
Protein structure
The FANCM protein comprises 2,048 amino acids organised into several functional domains that coordinate its DNA repair activities. The N-terminal region includes disordered segments (amino acids 1-45) followed by the helicase ATP-binding domain (amino acids 98-266), which contains the characteristic DEAH box motif (amino acids 214-217) essential for ATP-dependent DNA translocation. The helicase C-terminal domain (amino acids 452-627) completes the motor apparatus required for moving along DNA. A central region mediating interaction with CENPS/CENPSX (amino acids 661-800) suggests roles in coordinating repair with chromosome structure. The C-terminal half contains multiple disordered regions (amino acids 1433-1476, 1518-1540, and 1668-1809) that likely provide flexibility for protein-protein interactions. The extreme C-terminus (amino acids 1727-2048) mediates interaction with FAAP24, a binding partner critical for targeting FANCM to sites of DNA damage. This modular architecture allows FANCM to simultaneously engage DNA substrates and assemble multiprotein repair complexes.
Key variants
Genetic variants in FANCM range from rare biallelic mutations associated with Fanconi anaemia-like presentations to more common monoallelic variants linked to cancer predisposition. Pathogenic changes typically disrupt the protein's ability to bind DNA, hydrolyse ATP, or interact with repair complex partners. Loss-of-function variants can impair the cell's capacity to resolve replication fork stalling and repair interstrand crosslinks, leading to accumulation of chromosomal abnormalities.
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.1213C>T | p.Arg405Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1236_1237del | p.Leu412_Tyr413insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.1363_1366delinsCAAAGTTAAAGAAA | p.Glu455_Val456delinsGlnSerTer | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.2260C>T | p.Arg754Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.3088C>T | p.Arg1030Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.3235_3238del | p.Leu1080fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.4005del | p.Val1336fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.404_405dup | p.Lys136fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.4637T>G | p.Leu1546Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.865_881del | p.Lys288_Leu289insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Spermatogenic failure 28 |
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 FANCM have been associated with increased susceptibility to breast and ovarian cancer, particularly in individuals carrying a single pathogenic allele. Research also suggests a connection between FANCM variants and primary ovarian insufficiency, reflecting the protein's importance in maintaining genomic stability in reproductive tissues. Biallelic pathogenic variants, though rare, can result in more severe phenotypes characterised by bone marrow failure and developmental abnormalities, features overlapping with classical Fanconi anaemia. The spectrum of associated conditions reflects the protein's fundamental role in protecting cells from DNA damage across multiple organ systems.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic FANCM 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
Within the NHS Genomic Medicine Service, FANCM appears on several PanelApp panels with green classification status, indicating established clinical validity. The gene is included in panels for primary ovarian insufficiency, reflecting evidence for its role in female reproductive health. FANCM also features in the DDG2P resource, which catalogues genes associated with developmental disorders, and was incorporated into COVID-19 research panels exploring host genetic factors. These panel memberships reflect growing recognition of FANCM's clinical relevance beyond its original identification in rare DNA repair disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the FANCM gene do?
FANCM encodes a protein that detects DNA damage and coordinates the cellular repair response. It acts as a molecular motor that moves along DNA strands, recognising stalled replication forks and recruiting other proteins to fix damaged DNA before it leads to permanent mutations.
How is FANCM inherited?
FANCM follows an autosomal recessive inheritance pattern for severe phenotypes, meaning two pathogenic variants (one from each parent) are typically required for classical Fanconi anaemia-like presentations. However, carrying a single pathogenic variant may increase susceptibility to certain cancers and reproductive conditions.
Is FANCM testing available through the NHS?
FANCM testing may be available through NHS genomic services for individuals meeting specific clinical criteria, particularly those with relevant family histories of cancer or primary ovarian insufficiency. The gene's inclusion on NHS PanelApp panels indicates it is part of established testing pathways for certain clinical presentations, though access depends on individual clinical circumstances and referral criteria.