ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.466C>T (p.Arg156Trp) (rs779997419)

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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 RCV000167037 SCV000217861 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-16 criteria provided, single submitter clinical testing The p.R184W variant (also known as c.550C>T), located in coding exon 7 of the MUTYH gene, results from a C to T substitution at nucleotide position 550. The arginine at codon 184 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration (designated as p.R170W) was previously identified in conjunction with MUTYH alteration p.Y104C in an individual with adenomatous polyposis and colorectal cancer; however, functional effect and phase of the variants were not determined (Gómez-Fernández N et al. BMC Med. Genet. 2009 Jun;10:57). In addition, this alteration was also identified in conjunction with a second MUTYH alteration, p.Tyr104*, in an individual diagnosed with either colon cancer or polyps at age 66; however, the phase was unknown (Ricci MT et al. J. Hum. Genet. 2017 Feb;62:309-315). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000233436 SCV000285956 uncertain significance MYH-associated polyposis 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 184 of the MUTYH protein (p.Arg184Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs779997419, ExAC 0.001%). This variant was reported in an individual affected with multiple adenomas and colorectal cancer, and in an individual with suspected MUTYH-associated polyposis (PMID: 19531215, 27829682). Segregation studies were not performed and the clinical significance of this variant was not determined. This variant has also been reported as p.Arg170Trp. ClinVar contains an entry for this variant (Variation ID: 187318). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Counsyl RCV000233436 SCV000487355 uncertain significance MYH-associated polyposis 2016-05-10 criteria provided, single submitter clinical testing
GeneDx RCV000657000 SCV000566027 uncertain significance not provided 2018-08-03 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.550C>T at the cDNA level, p.Arg184Trp (R184W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). Using alternate nomenclature, this variant is also known as MUTYH c.508C>T, p.Arg170Trp (R170W). It has been reported to co-occur with a pathogenic MUTYH variant in an individual with colorectal cancer and polyps; however, the phase of the variants (in cis or trans) was unknown (Ricci 2017). This variant was also observed in an individual with 50-60 adenomas and colorectal cancer, who had a second unclassified variant in MUTYH (G?mez-Fern?ndez 2009). MUTYH Arg184Trp was not observed in at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MUTYH Arg184Trp 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 pathogenic variants on opposite chromosomes in MUTYH.?
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485428 SCV000601652 uncertain significance not specified 2016-11-22 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000485428 SCV000713011 uncertain significance not specified 2017-03-06 criteria provided, single submitter clinical testing The p.Arg184Trp variant in MUTYH has been reported, along with a second MUTYH va riant of uncertain significance (phase unknown), in one Spanish individual with multiple adenomas and colorectal cancer (Gomez-Fernandez 2009) and has also been reported in ClinVar (Variation ID# 187318). In addition, this variant has been identified in 1/66738 of European chromosomes by the Exome Aggregation Consortiu m (ExAC, http://exac.broadinstitute.org; dbSNP rs779997419). Although the p.Arg1 84Trp variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conser vation analysis do not provide strong support for or against an impact to the pr otein. In summary, the clinical significance of the p.Arg184Trp variant is uncer tain.
Color Health, Inc RCV000167037 SCV000911726 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-27 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 184 of the MUTYH protein. This variant is also known as c.508C>T (p.Arg170Trp) based on an alternative transcript (NM_001048171). Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals with suspected familial polyposis (PMID: 19531215, 27829682) and one of whom also has a pathogenic MUTYH covariant (PMID: 27829682). This variant has been identified in 3/246270 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000485428 SCV001361133 uncertain significance not specified 2019-10-10 criteria provided, single submitter clinical testing Variant summary: MUTYH c.550C>T (p.Arg184Trp) results in a non-conservative amino acid change located in the HhH-GPD domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251460 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.550C>T has been reported in the literature in individual with multiple adenomas and colorectal cancer (Gomez-Fernandez_2009) and in an individual suspected of MAP (Ricci_2016), both without strong evidence of causality. These reports do not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV001526816 SCV001737463 uncertain significance Familial multiple polyposis syndrome 2021-05-13 criteria provided, single submitter clinical testing The MUTYH c.466C>T (p.Arg156Trp) missense change has a maximum subpopulation frequency of 0.0031% in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/variant/1-45798461-G-A?dataset=gnomad_r2_1). Seven of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in two individuals with colorectal cancer who both had a second variant in MUTYH, one classified as pathogenic and one classified as of uncertain significance (PMID: 27829682, 19531215). In both individuals, the phase of the variants (in cis or in trans) was not known (PM3_supporting). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting, PM3_supporting, PP3.

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