ClinVar Miner

Submissions for variant NM_020937.4(FANCM):c.2586_2589del (p.Lys863fs) (rs768006618)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000657519 SCV000779255 likely pathogenic not provided 2018-05-15 criteria provided, single submitter clinical testing The c.2586_2589delAAAA variant in the FANCM gene has been reported previously in the homozygous state in an individual with B-cell precursor lymphoblastic leukemia diagnosed at 14 years old and who experienced treatment toxicity (Bogliolo et al., 2018). The c.2586_2589delAAAA variant causes a frameshift starting with codon Lysine 863, changes this amino acid to an Isoleucine residue, and creates a premature Stop codon at position 12 of the new reading frame, denoted p.Lys863IlefsX12. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.2586_2589delAAAA variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.2586_2589delAAAA as a likely pathogenic variant.
Invitae RCV000800840 SCV000940579 uncertain significance Fanconi anemia 2018-08-01 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys863Ilefs*12) in the FANCM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs768006618, ExAC 0.02%). This variant has been observed in the homozygous state in an individual with B-cell precursor lymphoblastic leukemia whose fibroblasts showed increased chromosome breakages and hypersensitivity to DNA-damaging drug treatment (PMID: 28837157). The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in FANCM cause disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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