ClinVar Miner

Submissions for variant NM_020937.4(FANCM):c.4352A>G (p.His1451Arg)

gnomAD frequency: 0.00008  dbSNP: rs572890751
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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 RCV000527822 SCV000626373 uncertain significance Fanconi anemia 2022-10-18 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1451 of the FANCM protein (p.His1451Arg). This variant is present in population databases (rs572890751, gnomAD 0.06%). 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: 456270). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 RCV001546018 SCV001765458 uncertain significance not provided 2024-08-09 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis indicates that this missense variant does not alter protein structure/function
Fulgent Genetics, Fulgent Genetics RCV002483359 SCV002790661 uncertain significance Spermatogenic failure 28; Premature ovarian failure 15 2021-12-29 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001546018 SCV004218800 uncertain significance not provided 2023-02-02 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.00055 (19/34488 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in a large breast cancer association study in individuals affected with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/FANCM). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

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