ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.652G>T (p.Val218Phe) (rs587780749)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123154 SCV000166458 likely pathogenic MYH-associated polyposis 2020-09-08 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 several individuals with MUTYH-associated polyposis (MAP) (PMID: 12606733, 19793053, 20687945). This variant is also known as c.694G>T, p.Val232Phe in the literature. ClinVar contains an entry for this variant (Variation ID: 135990). An experimental study reported this variant retained MUTYH protein function (PMID: 25820570). However, another experimental study have shown that this missense change results in reduced glycosylase activity and affects MUTYH protein function (PMID: 15673720). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000131615 SCV000186631 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-30 criteria provided, single submitter clinical testing The p.V246F variant (also known as c.736G>T) is located in coding exon 9 of the MUTYH gene, in the hMSH6-interacting domain. This alteration results from a G to T substitution at nucleotide position 736. The valine at codon 246 is replaced by phenylalanine, an amino acid with highly similar properties. The MSH6-interacting domain is conserved among the MUTY family members, and this amino acid position is partially conserved among MYH homologs of human, mouse, fission yeast, E. coli and B. stearothermophilus (Gu Y et al. J. Biol. Chem. 2002 Mar;277(13):11135-42; Bai H et al. Nucleic Acids Res. 2005 Jan;33(2):597-604). This alteration has been detected in multiple individuals with adenomatous polyposis who also carried another MUTYH mutation, including one individual with both polyposis and colorectal cancer (Sieber OM et al. N. Engl. J. Med. 2003 Feb;348(9):791-9; Filipe B et al. Clin. Genet. 2009 Sep:76(3):242–55; Gómez-Fernández N et al. BMC Med. Genet., 2009 Jun;10:57; López-Villar I et al. BMC Cancer. 2010 Aug;10:408). Functional analyses of the mutated protein revealed reduced glycosylase and DNA binding activities compared to the wild type enzyme (Bai H et al. Nucleic Acids Res. 2005 Jan;33(2):597-604). Of note, this alteration is also designated as p.V232F in the published literature. Based on protein sequence alignment, this amino acid position is conserved through mammals but poorly conserved in lower vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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.
Counsyl RCV000123154 SCV000487315 likely pathogenic MYH-associated polyposis 2015-12-01 criteria provided, single submitter clinical testing
Mendelics RCV000123154 SCV000837763 likely pathogenic MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131615 SCV000910970 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212707 SCV001134484 likely pathogenic not provided 2019-02-20 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Enriched in patients compared to ethnically matched controls. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Results on protein functions were conflicting.
Baylor Genetics RCV001292933 SCV001481636 likely pathogenic Pilomatrixoma 2019-09-25 criteria provided, single submitter clinical testing This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 12606733, 15673720, 25820570, 24733792, 28152038, 26556299; ClinVar: 135990]

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