ClinVar Miner

Submissions for variant NM_020937.4(FANCM):c.1972C>T (p.Arg658Ter) (rs368728266)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000513240 SCV000608699 likely pathogenic not provided 2020-02-01 criteria provided, single submitter clinical testing
Invitae RCV000705743 SCV000834756 pathogenic Fanconi anemia 2019-12-30 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the FANCM gene (p.Arg658*). It is expected to result in an absent or disrupted protein product, although an experimental study suggests that this variant may not cause nonsense-mediated mRNA decay (PMID: 31700994). This variant is present in population databases (rs368728266, ExAC 0.01%). This variant has been observed to be homozygous in an individual with breast cancer and other oncological malignancies and in an individual with breast cancer, pancytopenia, and chromosome fragility (PMID: 28837162). In addition, this variant has been observed to be heterozygous in individuals affected with ovarian cancer, polycythemia vera, and breast cancer (PMID: 21681190, 26822949, 29351780, 29287190, 28033443, 28881617); and in a large case-control study, this variant was observed more frequently in individuals with ER-negative breast cancer (OR=2.44, 95% CI [1.12-5.34], p=0.034) or triple-negative breast cancer (OR=3.79, 95% CI [1.56-9.18], p=0.009) than among controls (PMID: 31700994). ClinVar contains an entry for this variant (Variation ID: 444327). This variant disrupts the C-terminal domain of the FANCM protein, including the entire ERCC4 nuclease domain and the helix-hairpin-helix (HhH) motifs. These domains are critical for the interaction between FANCM and its DNA-binding partner FAAP24, as well as chromatin localization of the FANCM/FAAP24 complex and the activation of the FA core complex (PMID: 17289582, 23932590, 18174376, 19379763, 24003026). This variant has been reported to affect FANCM protein function (PMID: 31700994). For these reasons, this variant has been classified as Pathogenic.

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