ClinVar Miner

Submissions for variant NM_020937.4(FANCM):c.3827C>T (p.Ser1276Leu)

gnomAD frequency: 0.00004  dbSNP: rs753876341
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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 RCV000812710 SCV000953033 uncertain significance Fanconi anemia 2023-12-28 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1276 of the FANCM protein (p.Ser1276Leu). This variant is present in population databases (rs753876341, gnomAD 0.02%). 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: 656323). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine 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 RCV001568882 SCV001792831 uncertain significance not provided 2024-02-22 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed with FANCM p.(N1706T) in an adult with head and neck squamous cell carcinoma (PMID: 28678401); This variant is associated with the following publications: (PMID: 28678401, 33471991)
Fulgent Genetics, Fulgent Genetics RCV002507417 SCV002815690 uncertain significance Spermatogenic failure 28; Premature ovarian failure 15 2022-01-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001568882 SCV004218784 uncertain significance not provided 2023-09-14 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in individuals with breast cancer as well as healthy individuals in a large breast cancer association study (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/FANCM)). The frequency of this variant in the general population, 0.00021 (6/29106 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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