ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.1225C>T (p.Arg409Trp) (rs587778540)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206561 SCV000260004 uncertain significance MYH-associated polyposis 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 437 of the MUTYH protein (p.Arg437Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs587778540, ExAC 0.009%). This variant has not been reported in the literature in individuals with MUTYH-related disease. ClinVar contains an entry for this variant (Variation ID: 134864). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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.
Ambry Genetics RCV000214371 SCV000275427 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-20 criteria provided, single submitter clinical testing The p.R437W variant (also known as c.1309C>T), located in coding exon 13 of the MUTYH gene, results from a C to T substitution at nucleotide position 1309. The arginine at codon 437 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was detected by whole genome sequencing in an ancestrally diverse cohort of 681 healthy individuals (Bodian DL et al. PLoS One. 2014 Apr 11;9:e94554). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Clinical Services Laboratory,Illumina RCV000206561 SCV000357890 uncertain significance MYH-associated polyposis 2016-06-14 criteria provided, single submitter clinical testing
Counsyl RCV000206561 SCV000487384 uncertain significance MYH-associated polyposis 2016-10-26 criteria provided, single submitter clinical testing
GeneDx RCV000590752 SCV000566268 uncertain significance not provided 2018-03-16 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.1309C>T at the cDNA level, p.Arg437Trp (R437W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant was identified in 1/118 healthy Hispanic individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. MUTYH Arg437Trp was observed at an allele frequency of 0.017% (4/24,024) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in the NUDIX domain (Ruggieri 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether MUTYH Arg437Trp 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.?
Color Health, Inc RCV000214371 SCV000685565 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-10 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 437 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature but has been reported in a healthy individual (PMID: 24728327). This variant has been identified in 8/282742 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590752 SCV000697675 uncertain significance not provided 2016-02-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000121597 SCV000731384 uncertain significance not specified 2017-02-20 criteria provided, single submitter clinical testing The p.Arg437Trp variant in MUTYH has not been previously reported in individuals with MUTYH-associated polyposis but has been identified in 1/11568 of Latino ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs587778540). Although this variant has been seen in the general popu lation, its frequency is not high enough to rule out a pathogenic role. Computat ional prediction tools and conservation analysis do not provide strong support f or or against an impact to the protein. In summary, the clinical significance of the p.Arg437Trp variant is uncertain.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590752 SCV000888307 uncertain significance not provided 2017-11-02 criteria provided, single submitter clinical testing
ITMI RCV000121597 SCV000085794 not provided not specified 2013-09-19 no assertion provided reference population

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