ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.637C>T (p.Arg213Trp) (rs34126013)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164664 SCV000215329 pathogenic Hereditary cancer-predisposing syndrome 2018-11-17 criteria provided, single submitter clinical testing The p.R241W pathogenic mutation (also known as c.721C>T), located in coding exon 9 of the MUTYH gene, results from a C to T substitution at nucleotide position 721. The arginine at codon 241 is replaced by tryptophan, an amino acid with dissimilar properties. <span style="background-color:initial">This alteration has been reported in conjunction with the common MUTYH founder mutations p.G396D (p.G382D) and p.Y179C (p.Y165C)<span style="background-color:initial">, other pathogenic/likely pathogenic MUTYH variants, and as homozygous in multiple patients with classic polyposis, attenuated polyposis, and/or colorectal cancer (Isidro G et al. Hum Mutat. 2004 Oct;24(4):353-4; <span style="background-color:initial">Bai H et al. Nucleic Acids Res. 2005 Jan 26;33(2):597-604; Torrezan GT et al. Orphanet J Rare Dis. 2013 ;8:54; Guarinos C et al. Clin Cancer Res. 2014 Mar 1;20(5):1158-68; Win AK et al. Int J Cancer. 2016 Oct 1;139(7):1557-63; Khan N et al. Sci Rep. 2017 May 22;7(1):2214; Ambry internal data<span style="background-color:initial">). Furthermore, the aforementioned co-occurrences are likely to be in trans due to multiple observances with different pathogenic or likely pathogenic MUTYH variants.​ In functional assays measuring glycosylase activity and DNA-binding activity, this variant demonstrated impaired protein function similar to the p.Y179C (p.Y165C) MUTYH founder mutation (Bai H et al. Nucleic Acids Res. 2005 Jan 26;33(2):597-604; Komine K et al. Hum Mutat. 2015 Jul;36(7):704-11<span style="background-color:initial">). Of note, this alteration is also designated as p.R227W in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000235834 SCV000292738 pathogenic not provided 2019-01-04 criteria provided, single submitter clinical testing This pathogenic variant is denoted MUTYH c.721C>T at the cDNA level, p.Arg241Trp (R241W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant, also known as MUTYH Arg227Trp using an alternate reference sequence (NM_001048171.1), has been observed in individuals in the compound heterozygous state or homozygous state in individuals with multiple polyps and/or colorectal cancer (Fleischmann 2004, Isidro 2004, Torrezan 2013, Guarinos 2014). Functional studies have shown that this variant is deficient in glycosylase activity and partially deficient in base excision repair activity (Bai 2005, Komine 2015). MUTYH Arg241Trp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the MSH6 binding domain (Gu 2002, Ruggieri 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000369240 SCV000357900 likely pathogenic MYH-associated polyposis 2016-06-14 criteria provided, single submitter clinical testing The c.721C>T (p.Arg241Trp) variant, also referred to as c.679C>T (p.Arg227Trp), has been reported in five studies in which it is found in a total of six MYH-associated polyposis patients, including two siblings in a homozygous state and four patients in a compound heterozygous state with one of the common pathogenic MUTYH missense variants (Isidro et al. 2004; Fleischmann et al. 2004; Bai et al. 2005; Torrezan et al. 2013; Guarinos et al. 2014). The variant was absent from 354 controls (Fleischmann et al. 2004) but is reported at a frequency of 0.00042 in the South Asian population of the Exome Aggregation Consortium. Functional studies demonstrated that the p.Arg241Trp variant has a severe defect in adenine (A) /7,8-dihydro-8-oxo-guanine binding and therefore in the ability to catalyze adenine excision from A/GO mismatches, one of the main functions of the protein. The p.Arg241Trp variant was also shown to have no detectable glycosylase activity and failed to complement mut Y-deficiency in E. coli. The variant does not affect binding to the hMSH2/hMSH6 complex (Bai et al. 2005; Komine et al. 2015). Based on the collective evidence, the p.Arg241Trp variant is classified as likely pathogenic for MYH-associated polyposis.
Invitae RCV000369240 SCV000545770 likely pathogenic MYH-associated polyposis 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 241 of the MUTYH protein (p.Arg241Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs34126013, ExAC 0.04%). This variant has been reported as heterozygous with another pathogenic variant in MUTYH in multiple individuals affected with polyposis and/or colorectal cancer (PMID: 24470512, 14991577, 27194394), and as homozygous in two siblings from a family affected with polyposis (PMID: 23561487). This variant is also known as c.679C>T (p.Arg227Trp) in the literature. ClinVar contains an entry for this variant (Variation ID: 185274). This variant has been reported to affect MUTYH protein function (PMID: 15673720, 25820570). This variant disrupts the p.Arg241 amino acid residue in MUTYH. Other variant(s) that disrupt this residue have been observed in individuals with MUTYH-related conditions (PMID: 19732775, Invitae), which suggests that this may be a clinically significant amino acid residue. 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.
Counsyl RCV000369240 SCV000678194 likely pathogenic MYH-associated polyposis 2017-01-04 criteria provided, single submitter clinical testing
Color Health, Inc RCV000164664 SCV000685663 likely pathogenic Hereditary cancer-predisposing syndrome 2020-02-04 criteria provided, single submitter clinical testing
Mendelics RCV000369240 SCV000837764 pathogenic MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235834 SCV001134483 pathogenic not provided 2018-09-04 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000235834 SCV001248084 pathogenic not provided 2018-10-01 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000235834 SCV001450150 likely pathogenic not provided 2015-06-16 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000235834 SCV000592694 pathogenic not provided no assertion criteria provided clinical testing The MUTYH p.Arg241Trp variant was identified in 2 of 822 proband chromosomes from individuals with colorectal adenomas (Isidro 2004, Fleischmann 2004). In both cases the variant occurred as a biallelic mutation in combination with the pathogenic MUTYH p.Gly382Asp mutation. The p.Arg241Trp variant was also identified in dbSNP (ID: rs34126013), HGMD, UMD (4X as a causal variant), and the “InSiGHT Colon Cancer Database”. The p.Arg241 residue is conserved across mammals and more distantly related organisms and 5/5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Arg241Trp variant may impact the protein. In addition, one functional study found the variant to be severely defective in A/8-oxoG binding and glycosylase activities, and it failed to complement MutY-deficiency in E.coli (Bai 2005). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Clinical Genetics,Academic Medical Center RCV000235834 SCV001921182 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000235834 SCV001958080 pathogenic not provided no assertion criteria provided clinical testing

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