ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.719C>T (p.Ala240Val) (rs369120013)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656909 SCV000211404 uncertain significance not provided 2018-11-01 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.719C>T at the cDNA level, p.Ala240Val (A240V) at the protein level, and results in the change of an Alanine to a Valine (GCA>GTA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MUTYH Ala240Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). MUTYH Ala240Val is located in the MSH6 binding domain (Gu 2002, 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 information, it is unclear whether MUTYH Ala240Val is pathogenic or benign. 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.
Ambry Genetics RCV000160753 SCV000218277 likely benign Hereditary cancer-predisposing syndrome 2018-03-01 criteria provided, single submitter clinical testing In silico models in agreement (benign) ;Other strong data
Invitae RCV000458598 SCV000545717 uncertain significance MYH-associated polyposis 2020-08-06 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 240 of the MUTYH protein (p.Ala240Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs369120013, 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: 182690). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The valine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000212705 SCV000601658 uncertain significance not specified 2017-06-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000160753 SCV001342785 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-24 criteria provided, single submitter clinical testing This missense variant replaces alanine with valine at codon 240 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/250490 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.

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