ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.346C>T (p.Arg116Trp) (rs373766973)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132238 SCV000187321 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-27 criteria provided, single submitter clinical testing The p.R116W variant (also known as c.346C>T), located in coding exon 3 of the MUTYH gene, results from a C to T substitution at nucleotide position 346. The arginine at codon 116 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site. RNA studies have demonstrated this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). 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.
GeneDx RCV000656907 SCV000211399 uncertain significance not provided 2018-06-29 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.346C>T at the cDNA level, p.Arg116Trp (R116W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MUTYH Arg116Trp was observed at an allele frequency of 0.01% (3/30,782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. While protein-based in silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function, multiple splicing models predict that this variant may damage the natural splice donor site for intron 3 and possibly cause abnormal gene splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether MUTYH Arg116Trp 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.?
Invitae RCV000195451 SCV000254709 uncertain significance MYH-associated polyposis 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 116 of the MUTYH protein (p.Arg116Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs373766973, ExAC 0.02%). This variant has not been reported in the literature in individuals with a MUTYH-related disease. ClinVar contains an entry for this variant (Variation ID: 142812). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0. The tryptophan amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212698 SCV000601646 uncertain significance not specified 2017-01-17 criteria provided, single submitter clinical testing
Color Health, Inc RCV000132238 SCV000685611 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-30 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 116 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 17/282866 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 RCV000212698 SCV000919791 uncertain significance not specified 2017-10-23 criteria provided, single submitter clinical testing Variant summary: The MUTYH c.346C>T (p.Arg116Trp) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 17/277200 control chromosomes at a frequency of 0.0000613, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353576 SCV000592681 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The MYH p.Arg116Trp variant is a missense change in exon 3, and is conserved across mammals/species and computational analyses (PolyPhen, SIFT) suggest that this variant may impact the protein. The variant occurs in the last three bases of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. A modest alteration in the splice predition was observed by one of the five prediction programs used. However, the above evidence is not predictive enough to assume pathogenicity or rule out pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty at this time.

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