ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.736G>A (p.Val246Ile) (rs587780749)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222948 SCV000277854 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-13 criteria provided, single submitter clinical testing The p.V246I variant (also known as c.736G>A), located in coding exon 9 of the MUTYH gene, results from a G to A substitution at nucleotide position 736. The valine at codon 246 is replaced by isoleucine, an amino acid with highly similar properties. This variant occurs in the hMSH6-interacting domain of the MUTYH protein (Gu Y et al. J Biol Chem. 2002 Mar 29;277(13):11135-42; Bai H et al. Nucleic Acids Res. 2005 Jan 26;33(2):597-604). This amino acid position is well conserved through mammals, but not in lower 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 RCV000475824 SCV000545728 uncertain significance MYH-associated polyposis 2020-09-03 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 246 of the MUTYH protein (p.Val246Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs587780749, ExAC 0.002%). This variant has not been reported in the literature in individuals with MUTYH-related disease. ClinVar contains an entry for this variant (Variation ID: 233479). 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 tolerated, 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.
GeneDx RCV000590172 SCV000571337 uncertain significance not provided 2018-06-26 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.736G>A at the cDNA level, p.Val246Ile (V246I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MUTYH Val246Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the MSH6 binding domain (Ruggieri 2013). 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 Val246Ile 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001549280 SCV000697709 uncertain significance not specified 2021-07-26 criteria provided, single submitter clinical testing Variant summary: MUTYH c.736G>A (p.Val246Ile) results in a conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250286 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.736G>A in individuals affected with MUTYH-Associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Health, Inc RCV000222948 SCV000905862 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-30 criteria provided, single submitter clinical testing

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