ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.1442G>A (p.Arg481His) (rs144111588)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131561 SCV000186565 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-21 criteria provided, single submitter clinical testing ​The p.R495H variant (also known as c.1484G>A), located in coding exon 15 of the MUTYH gene, results from a G to A substitution at nucleotide position 1484. The arginine at codon 495 is replaced by histidine, an amino acid with highly similar properties. In one functional study, this variant demonstrated DNA glycosylase activity similar to that of wild type MUTYH in a DNA cleavage activity assay and a supF forward mutation assay (Shinmura K et al. Hum. Mutat. 2016 Apr;37:350-3). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000231615 SCV000285933 uncertain significance MYH-associated polyposis 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 495 of the MUTYH protein (p.Arg495His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs144111588, ExAC 0.02%). This variant has been observed in an individual affected with endometrial cancer (PMID: 27443514). ClinVar contains an entry for this variant (Variation ID: 142440). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). 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 RCV000656913 SCV000292631 uncertain significance not provided 2018-08-13 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.1484G>A at the cDNA level, p.Arg495His (R495H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MUTYH Arg495His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Nudix hydrolase domain (Ruggieri 2013, UniProt). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MUTYH Arg495His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two MUTYH pathogenic variants on opposite chromosomes.
Counsyl RCV000231615 SCV000487360 uncertain significance MYH-associated polyposis 2016-06-04 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131561 SCV000685589 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-16 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 495 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual affected with endometrial cancer (PMID: 26832770, 27443514) and reported to occur in 0.12% of the Japanese population (PMID: 26694661). This variant has been identified in 8/272492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656913 SCV000889523 uncertain significance not provided 2018-02-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000236240 SCV000917799 uncertain significance not specified 2017-11-24 criteria provided, single submitter clinical testing Variant summary: The MUTYH c.1484G>A (p.Arg495His) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 9/267106 control chromosomes at a frequency of 0.0000337, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0055902). The variant has been reported in Lynch Syndrome patients in the literature, one in the tumor of a patient who carried a likely pathogenic MSH2 germline variant, as well as in the germline of a patient carrying a pathogenic MSH6 variant (Vargas-Parra_2017, Ring_2016). However, due to the predominantly recessive mode of inheritance attributed to variants in MUTYH, the possibility of incidental carrier status for a pathogenic variant cannot be excluded. The DNA glycosylase activity and ability to suppress mutations caused by 8-hydroxyguanine, an oxidized form of guanine, were examined for the nine variants of type 2 MUTYH, a nuclear form of the enzyme, by DNA cleavage activity assay and supF forward mutation assay, respectively. The variant was similar to WT in DNA glycosylase activity and mutation frequency of the supF gene. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353893 SCV000592720 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The p.Arg495His variant was not identified in the literature. This residue is conserved in mammals but not lower organisms such as chicken or zebrafish where a Lysine (Lys) is present at this position. In addition, computational analyses (PolyPhen, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein, but this information is not very predictive of pathogenicity. This variant was identified in the dbSNP database (ID: rs144111588) but was not validated and in the exome variant server in a European cohort with a frequency of 0.00023 increasing the likelihood that this may be a low frequency rare variant in this population of origin. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.
GenomeConnect - Invitae Patient Insights Network RCV000231615 SCV001749558 not provided MYH-associated polyposis no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 06-04-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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