ClinVar Miner

Submissions for variant NM_020937.4(FANCM):c.4367G>A (p.Arg1456His)

gnomAD frequency: 0.00008  dbSNP: rs749332566
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000538157 SCV000626374 uncertain significance Fanconi anemia 2022-11-01 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1456 of the FANCM protein (p.Arg1456His). This variant is present in population databases (rs749332566, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with FANCM-related conditions. ClinVar contains an entry for this variant (Variation ID: 456271). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
GeneDx RCV001552330 SCV001772999 uncertain significance not provided 2024-04-30 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31133750, 28881617, 35982159)
CeGaT Center for Human Genetics Tuebingen RCV001552330 SCV005330883 uncertain significance not provided 2024-08-01 criteria provided, single submitter clinical testing FANCM: PM2, PS4:Supporting, BP1, BP4
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001552330 SCV005626309 uncertain significance not provided 2024-07-02 criteria provided, single submitter clinical testing The FANCM c.4367G>A (p.Arg1456His) variant has been identified in the published literature in individuals with breast cancer and reportedly healthy individuals (PMID: 36707629 (2023), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/FANCM)). The frequency of this variant in the general population, 0.000094 (12/128092 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

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