ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.1259C>T (p.Thr420Met) (rs587780084)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235188 SCV000149666 uncertain significance not provided 2018-06-28 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.1301C>T at the cDNA level, p.Thr434Met (T434M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant was identified in an individual with a personal history of a Lynch syndrome-associated cancer and/or polyps who underwent genetic testing for Lynch syndrome using a multi-gene panel (Yurgelun 2015). MUTYH Thr434Met was observed at an allele frequency of 0.009% (2/24,026) 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MUTYH Thr434Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two MUTYH pathogenic variants on opposite chromosomes.
Ambry Genetics RCV000115757 SCV000184172 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-02 criteria provided, single submitter clinical testing The p.T434M variant (also known as c.1301C>T), located in coding exon 13 of the MUTYH gene, results from a C to T substitution at nucleotide position 1301. The threonine at codon 434 is replaced by methionine, an amino acid with similar properties. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology 2015 Sep;149(3):604-613.e20). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000411291 SCV000487339 uncertain significance MYH-associated polyposis 2016-03-03 criteria provided, single submitter clinical testing
Invitae RCV000411291 SCV000639269 uncertain significance MYH-associated polyposis 2020-10-23 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 434 of the MUTYH protein (p.Thr434Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs587780084, ExAC 0.009%). This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145) as well as in an individual undergoing Lynch syndrome genetic testing (PMID: 25980754). This variant is also known as c.1259C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 127837). 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 methionine 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. 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.
Color Health, Inc RCV000115757 SCV000690516 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-20 criteria provided, single submitter clinical testing This missense variant replaces threonine with methionine at codon 434 of the MUTYH protein. This variant is also known as c.1259C>T (p.Thr420Met) based on the NM_001048171.1 transcript. 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 been reported in an individual suspected of having Lynch syndrome (PMID: 25980754) and in an individual affected with colorectal cancer (PMID: 28135145). This variant has also been identified in 11/282736 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235188 SCV000888306 uncertain significance not provided 2018-08-13 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.