ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.736G>T (p.Val246Phe) (rs587780749)

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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 RCV000131615 SCV000186631 likely pathogenic Hereditary cancer-predisposing syndrome 2017-12-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function by in vitro/ex vivo assay,Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous,In silico models in agreement (benign)
Color RCV000131615 SCV000910970 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
Counsyl RCV000123154 SCV000487315 likely pathogenic MYH-associated polyposis 2015-12-01 criteria provided, single submitter clinical testing
GeneDx RCV000212707 SCV000211406 likely pathogenic not provided 2018-09-18 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.736G>T at the cDNA level, p.Val246Phe (V246F) at the protein level, and results in the change of a Valine to a Phenylalanine (GTC>TTC). This variant, also known as Val232Phe using alternate nomenclature, has been observed in conjunction with a MUTYH founder pathogenic variant in several individuals with multiple polyps and/or colorectal cancer (Sieber 2003, Filipe 2009, Lopez-Villar 2010). Although functional studies examining the ability to suppress mutation rates in MutY-deficient E. coli have been mixed, other assays have shown that MUTYH Val246Phe causes reduced glycosylase and DNA-binding activity as compared to wild type (Bai 2005, Komine 2015). MUTYH Val246Phe was observed at an allele frequency of 0.039% (13/33,566 alleles) in individuals of Latino ancestry in large population cohorts (Lek 2016). MUTYH Val246Phe 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 the current evidence, we consider this variant to be a likely pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000123154 SCV000357899 uncertain significance MYH-associated polyposis 2016-06-14 criteria provided, single submitter clinical testing The c.694G>T (p.Val232Phe) variant has been reported in three studies and is found in three patients with MYH-associated polyposis, including two in a compound heterozygous state and in one patient allele where zygosity was not specified (Seiber et al. 2003; Gomez-Fernandez et al. 2009; Lopez-Villar et al. 2010). The p.Val232Phe variant was absent from at least 107 controls but is reported at a frequency of 0.00009 in the Latino population of the Exome Aggregation Consortium, but this is based on one allele in an area of poor sequence coverage. Two studies have provided in vitro functional analysis in E. coli cells, and the results were somewhat conflicting. Bai et al. (2005) demonstrated that the p.Val232Phe variant resulted in an 89% reduction in glycosylase activity compared to wild type after adjusting for protein concentrations. Additionally, in cells transfected with the p.Val232Phe variant, DNA binding affinity of MYH was reduced to approximately two percent compared with the wild type enzyme. However, Komine et al. (2015) utilized a different E. coli complementation method and concluded that the functionality of the p.Val232Phe variant was retained compared to wild type. Taking into consideration both the patient data and conflicting functional evidence, the p.Val232Phe variant is classified as a variant of unknown significance but suspicious for pathogenicity for MYH-associated polyposis.
Invitae RCV000123154 SCV000166458 uncertain significance MYH-associated polyposis 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces valine with phenylalanine at codon 246 of the MUTYH protein (p.Val246Phe). The valine residue is moderately conserved and there is a small physicochemical difference between valine and phenylalanine. This variant is present in population databases (rs587780749, ExAC 0.009%). This variant has been reported together with other pathogenic MUTYH variants in individuals affected with MUTYH-associated polyposis (MAP) (PMID: 12606733, 19793053, 20687945) and in heterozygous individuals affected with breast cancer and colorectal cancer (PMID: 24733792, 19531215). This variant is also known as c.694G>T, p.Val232Phe in the literature. ClinVar contains an entry for this variant (Variation ID: 135990). Experimental studies have shown that this missense change results in reduced glycosylase activity and in a partially defective MUTYH protein in an E.coli complementation assay (PMID: 15673720). However, another experimental study using an E.coli complementation assay reported this variant retained MUTYH function (PMID: 25820570). 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.
Mendelics RCV000123154 SCV000837763 likely pathogenic MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing

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