FANCM – Breast Cancer

FANCM encodes a DNA translocase involved in interstrand crosslink repair and fork remodeling. Heterozygous loss-of-function (LoF) variants in FANCM have been reported in multiple case-control and familial studies demonstrating elevated breast cancer risk, particularly for ER-negative and triple-negative subtypes. The association is supported by both large population cohorts and mechanistic functional data, consistent with a moderate-penetrance cancer predisposition gene.

Genetic Evidence

Multiple large cohort and case-control studies have identified truncating FANCM variants enriched in breast cancer cases versus controls. In a Finnish series of 3 933 invasive cases, 101 carriers of the recurrent nonsense variant c.5101C>T (p.Gln1701Ter) showed poorer 10-year survival (HR = 1.66) and reduced tumour PAR activity (PMID:27542569). A JAMA Oncology study screened 2 047 familial BC index cases (BRCA1/2 negative) and 2 187 controls, finding heterozygous LoF mutations in 1.03% of cases with an overall OR = 2.05 for familial breast cancer and OR = 3.75 for TNBC (PMID:28033443). Large meta-analyses confirm associations for c.5791C>T (p.Arg1931Ter) with familial risk (OR≈3.3) and mechanistic splicing defects (PMID:26130695).

Variant Spectrum & Inheritance

Breast cancer predisposition is conferred by heterozygous LoF variants (frameshift, nonsense, canonical splice) with an autosomal dominant pattern and incomplete penetrance. Key recurrent alleles include c.5101C>T (p.Gln1701Ter), c.5791C>T (p.Arg1931Ter), and c.1972C>T (p.Arg658Ter). Carrier frequencies range from 1–4% in high-risk European populations and are higher in TNBC cohorts. No clear founder effect outside Northern Europe has been established.

Functional Evidence

In vitro and cellular assays demonstrate that LoF FANCM variants abrogate DNA repair and fork rescue functions. The p.Arg1931Ter mutation induces exon skipping and loss of DNA repair activity in complementation assays (PMID:26130695). Patient-derived fibroblasts with p.Arg658Ter and p.Gln1701Ter show increased chromosomal fragility and hypersensitivity to crosslinking agents and olaparib, confirming a loss-of-function mechanism (PMID:31700994).

Conflicting Evidence

A South American case–control study of 492 BRCA1/2-negative cases and 673 controls found no significant association for rs144567652 (p.Arg1931Ter) or rs147021911 (p.Gln1701Ter), suggesting population-specific effects or limited power (PMID:36835452).

Integration & Clinical Utility

Collectively, genetic and functional data fulfill ClinGen criteria for a strong gene–disease association. FANCM LoF variants confer a 2–4-fold increased risk of ER-negative and triple-negative breast cancer through haploinsufficiency–mediated repair deficiency. These variants are detectable by panel testing and inform risk stratification, surveillance, and therapeutic decisions including PARP inhibitor responsiveness.

Key Take-home: Heterozygous FANCM truncating variants are moderate-penetrance breast cancer risk factors, especially for ER-negative subtypes, and warrant inclusion in clinical gene panels.

References

• International Journal of Cancer • 2016 • FANCM c.5101C>T mutation associates with breast cancer survival and treatment outcome. PMID:27542569
• JAMA Oncology • 2017 • Association Between Loss-of-Function Mutations Within the FANCM Gene and Early-Onset Familial Breast Cancer. PMID:28033443
• Human Molecular Genetics • 2015 • FANCM c.5791C>T nonsense mutation (p.Arg1931) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor.* PMID:26130695
• NPJ Breast Cancer • 2019 • The FANCM:p.Arg658 truncating variant is associated with risk of triple-negative breast cancer.* PMID:31700994
• International Journal of Molecular Sciences • 2023 • Association of FANCM Mutations with Familial and Early-Onset Breast Cancer Risk in a South American Population. PMID:36835452

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