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FANCM – Fanconi anemia

FANCM has been implicated in Fanconi anemia (FA) through autosomal recessive inheritance, but the clinical validity is limited due to scarce patient data. To date, a single adult case with homozygous FANCM c.1511_1515del (p.Arg504AsnfsTer29) presented with FA-like chromosomal instability yet lacked classical hematological features such as pancytopenia or bone marrow failure (PMID:34793962). No segregation beyond the index individual has been documented, and biallelic FANCM mutations more frequently underlie cancer predisposition syndromes distinct from bona fide FA (PMID:28837157). Consequently, current genetic evidence remains insufficient to support a definitive role of FANCM in FA pathogenesis.

Despite limited genetic data, moderate experimental evidence supports FANCM’s mechanistic role in interstrand crosslink repair and replication fork remodeling. Structural analysis of the FANCM–FAAP24 complex revealed DNA-binding domains essential for damage recognition (PMID:23932590), and functional assays in Drosophila and human cells demonstrate hypersensitivity to crosslinking agents and defective ATR/Chk1 checkpoint signaling upon FANCM depletion (PMID:18995830). These concordant findings affirm FANCM’s contribution to the FA pathway but underscore that biallelic loss-of-function often manifests as cancer susceptibility rather than classical marrow failure.

Key Take-home: While functional studies confirm FANCM’s role in DNA repair, insufficient case-level evidence currently precludes its routine use in FA diagnosis outside research settings.

References

  • European journal of medical genetics • 2022 • Fanconi-like anemia related to a FANCM mutation. PMID:34793962
  • Genetics in medicine • 2018 • Biallelic truncating FANCM mutations cause early-onset cancer but not Fanconi anemia. PMID:28837157
  • Structure • 2013 • Architecture and DNA recognition elements of the Fanconi anemia FANCM-FAAP24 complex. PMID:23932590
  • Molecular cell • 2008 • FANCM and FAAP24 function in ATR-mediated checkpoint signaling independently of the Fanconi anemia core complex. PMID:18995830

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

One proband with homozygous FANCM variant presenting FA-like features without classic hematological manifestations; no segregation across families; genetic heterogeneity of FA

Genetic Evidence

Limited

One biallelic FANCM variant reported in AR inheritance; no additional family segregation (1 proband)

Functional Evidence

Moderate

Multiple in vitro and in vivo functional studies (e.g., Drosophila, structural, cell assays) demonstrate FANCM’s essential role in interstrand crosslink repair and replication fork remodeling