ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.1483C>T (p.Arg495Cys)

gnomAD frequency: 0.00016  dbSNP: rs147480076
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165016 SCV000215711 likely benign Hereditary cancer-predisposing syndrome 2018-11-29 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp RCV000229869 SCV000285938 uncertain significance Familial adenomatous polyposis 2 2024-01-30 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 523 of the MUTYH protein (p.Arg523Cys). This variant is present in population databases (rs147480076, gnomAD 0.02%). This missense change has been observed in individual(s) with colon polyposis, colorectal cancer, breast cancer, ovarian cancer and/or pancreatic cancer (PMID: 27829682, 34347074, 34371384). This variant is also known as c.1525C>T (p.Arg509Cys). ClinVar contains an entry for this variant (Variation ID: 185573). 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 cysteine 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.
PreventionGenetics, part of Exact Sciences RCV004528913 SCV000806348 uncertain significance MUTYH-related disorder 2023-12-04 criteria provided, single submitter clinical testing The MUTYH c.1567C>T variant is predicted to result in the amino acid substitution p.Arg523Cys. This variant has been reported in an individual with MUTYH-associated polyposis and interpreted as uncertain significance (Table 1, Ricci et al. 2017. PubMed ID: 27829682). This variant is reported in 0.024% of alleles in individuals of European (Finnish) descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/185573/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Color Diagnostics, LLC DBA Color Health RCV000165016 SCV000902831 likely benign Hereditary cancer-predisposing syndrome 2016-10-17 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000679426 SCV001147262 uncertain significance not provided 2021-01-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175587 SCV001339223 uncertain significance not specified 2023-09-26 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1567C>T (p.Arg523Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-05 in 251480 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (9.1e-05 vs 0.0046), allowing no conclusion about variant significance. c.1567C>T has been reported in the literature in sequencing studies of individuals with a suspected diagnosis of MUTYH-associated Polyposis and among patients with colorectal cancer (example, Ricci_2017, Yurgelun_2017, Biscaglia_2022). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. Co-occurrence with other pathogenic variant(s) have been reported (CHEK2 c.470T>C , p.ile157Thr), providing supporting evidence for a benign role (Biscaglia_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27829682, 28135145, 34347074, 36243179). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=7) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679426 SCV001470029 uncertain significance not provided 2023-07-08 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in individuals suspected MUTYH-associated polyposis (PMID: 27829682 (2016)), breast cancer (PMID: 34371384 (2021)), or colorectal cancer (PMIDs: 34347074 (2022), 28135145 (2017)). The frequency of this variant in the general population, 0.00024 (6/25122 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.
Sema4, Sema4 RCV000165016 SCV002532256 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-06 criteria provided, single submitter curation
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000679426 SCV003799625 uncertain significance not provided 2022-04-06 criteria provided, single submitter clinical testing The MUTYH c.1567C>T; p.Arg523Cys variant (rs147480076) is described in the literature in cohorts of individuals affected with polyposis and/or colorectal cancer, but the pathogenicity in both studies have not been ascertained (Ricci 2017, Yurgelun 2017). It is reported in ClinVar (Variation ID: 185573), and is observed in the general population at an overall frequency of 0.01% (25/282876 alleles) in the Genome Aggregation Database. The arginine at codon 523 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.166). Given the lack of clinical and functional data, the significance of the p.Arg523Cys variant is uncertain at this time. REFERENCES Ricci et al. Type and frequency of MUTYH variants in Italian patients with suspected MAP: a retrospective multicenter study. J Hum Genet. 2017 Feb;62(2):309-315. PMID: 27829682. Yurgelun et al. Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. J Clin Oncol. 2017 Apr 1;35(10):1086-1095. PMID: 28135145.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV001175587 SCV004024857 uncertain significance not specified 2024-07-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV000229869 SCV004198809 uncertain significance Familial adenomatous polyposis 2 2024-03-14 criteria provided, single submitter clinical testing

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