Cytopenias and congenital anaemias

Gene: FANCM

Publication PMID: 28837162 entitled: “Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility.” In this study breast cancer probands were investigated for DNA damage response genes, and 5 cases had FANCM loss-of-function variants. They showed a heterogeneous phenotype including cancer predisposition, toxicity to chemotherapy, early menopause, and possibly chromosome fragility. The phenotype severity might correlate with mutation position in the gene. They authors conclude: “Our data indicate that biallelic FANCM mutations do not cause classical FA, providing proof that FANCM is not a canonical FA gene. Moreover, our observations support previous findings suggesting that FANCM is a breast cancer-predisposing gene. Mutation testing of FANCM might be considered for individuals with the above-described clinical features.”

Created: 2 Nov 2017, 2:19 p.m.

Red List (low evidence)

Comment when marking as ready: Insufficient evidence at present for causation in isolation

Created: 28 Feb 2017, 1:41 p.m.

Comment on list classification: See reviews for discussion of relative evidence for and against causation. The consensus on discussion amongst curation team was that the evidence presented suggests perhaps digenic contribution (FANCA / FANCM) in a patient. Therefore evidence not considered sufficient for inclusion. Await further reports.

Created: 28 Feb 2017, 1:40 p.m.

No current OMIM associated phenotype. Please see comprehensive assessment of the current evidence by Rebecca Foulger. In addition email correspondence with Noemi Roy, who has discussed with Inderjeet Dokal, an expert in this condition and the genes that are thought to be involved. He is aware of one family with compound het mutations in FANCM and FANCA.

It is possible that this gene is related to Fanconi anaemia but based upon the current evidence in my opinion it cannot be included for useful filtering of variants on a diagnostic basis unless further evidence of causation is identified.

Created: 28 Feb 2017, 9:51 a.m.

Mode of inheritance
Unknown

Publications

• 16116422
• 19423727
• 25078778

Further evidence that FANCM is not a fanconi anaemia gene comes from PMID:25078778: in a large exome-sequencing study and study of hospital records Lim et al., 2014 (PMID:25078778) did NOT find evidence to support FANCM as a gene associated with Fanconi anemia.

Created: 9 Feb 2017, 1:26 p.m.

FANCM was named as a Fanconi anemia gene based on Meetei et al., 2005 (PMID:16116422) who identified compound heterozygous variants in the FANCM gene in a cell line derived from a patient with Fanconi anemia.

However, in cell lines derived from the 2 sibs originally reported by Meetei et al., Singh et al., 2009 (PMID:19423727) identified biallelic mutations in the FANCA gene. They also noted that only 1 of the sibs had clinical features of the disorder and that the clinically affected sib carried only 1 of the FANCM variants. The clinically unaffected sib carried both biallelic FANCA mutations and biallelic FANCM variants. Singh et al. (2009) reclassified the affected sib as having FANCA.

Created: 9 Feb 2017, 1:26 p.m.

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Fanconi anemia

Publications

• 16116422

Variants in this GENE are reported as part of current diagnostic practice