ClinVar Miner

Submissions for variant NM_020937.4(FANCM):c.1393A>T (p.Asn465Tyr)

gnomAD frequency: 0.00001  dbSNP: rs776166350
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001217436 SCV001389276 uncertain significance Fanconi anemia 2024-01-08 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 465 of the FANCM protein (p.Asn465Tyr). This variant is present in population databases (rs776166350, 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: 946550). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 RCV002276663 SCV002567612 uncertain significance not provided 2022-02-17 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge
Quest Diagnostics Nichols Institute San Juan Capistrano RCV002276663 SCV005626243 uncertain significance not provided 2024-10-09 criteria provided, single submitter clinical testing The FANCM c.1393A>T (p.Asn465Tyr) variant has been reported in the published literature in an individual with ovarian cancer (PMID: 34326862 (2021)). The frequency of this variant in the general population, 0.00016 (3/18386 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 conflicting predictions that this variant is benign or damaging. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on FANCM mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Based on the available information, we are unable to determine the clinical significance of this variant.

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