ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.734G>A (p.Arg245His) (rs140342925)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129105 SCV000183816 pathogenic Hereditary cancer-predisposing syndrome 2017-09-27 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,Other strong data supporting pathogenic classification
Color RCV000129105 SCV000537663 pathogenic Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing
Counsyl RCV000196778 SCV000487344 likely pathogenic MYH-associated polyposis 2016-03-31 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000196778 SCV000592696 likely pathogenic MYH-associated polyposis 2014-12-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515198 SCV000611287 pathogenic MYH-associated polyposis; Pilomatrixoma; Neoplasm of stomach 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000212706 SCV000211405 pathogenic not provided 2019-01-16 criteria provided, single submitter clinical testing This pathogenic variant is denoted MUTYH c.734G>A at the cDNA level, p.Arg245His (R245H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant, also known as MUTYH Arg231His using an alternative reference sequence (NM_001048171.1), has been observed in the compound heterozygous or homozygous state in numerous individuals with a history of polyps and/or colon cancer (Aceto 2005, Piccioli 2006, Olschwang 2007, Russell 2006, Vogt 2009, Win 2014, Papp 2016, Viel 2017, Ricci 2017). Functional studies have shown that this variant results in decreased MUTYH protein expression, impaired glycosylase activity, and an increase in spontaneous mutation events (Ali 2008, Ruggieri 2013, Grasso 2014. Komine 2015). MUTYH Arg245His was observed at an allele frequency of 0.03% (5/18,840 alleles) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in the FeS cluster (Ruggieri 2013). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, we consider MUTYH Arg245His to be pathogenic.
GeneKor MSA RCV000129105 SCV000821746 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781618 SCV000919794 pathogenic MUTYH-associated polyposis 2017-09-07 criteria provided, single submitter clinical testing Variant summary: The MUTYH c.734G>A (p.Arg245His) variant causes a missense change involving the alteration of a conserved nucleotide located in the DNA glycosylase domain and the Helix-turn-helix, base-excision DNA repair, C-terminal domain of the protein (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional assays showed the variant to be associated with defective glycosylase and DNA binding activity and concluded that this variant is functionally defective (Ali_2008, Komine_2015).The variant was found in the control population dataset of ExAC in 16/119648 control chromosomes at a frequency of 0.0001337, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644). This variant has been reported in numerous MUTYH-associated polyposis patients, in both homozygotes and compound heterozygotes (Aceto_2005, Vogt_2009). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000196778 SCV000253868 pathogenic MYH-associated polyposis 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 245 of the MUTYH protein (p.Arg245His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs140342925, ExAC 0.02%). This variant has been reported as homozygous or as compound heterozygous in several individuals affected with familial adenomatous polyposis and colorectal cancer (PMID: 16134147, 19732775, 23108399, 24444654, 26446593, 16557584). This variant is also known as c.692G>A (p.Arg231His) in the literature. ClinVar contains an entry for this variant (Variation ID: 140877). Experimental studies have shown that this variant severely affects several aspects of MUTYH protein function (PMID: 18534194, 17081686, 23108399, 24569162, 25820570). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212706 SCV000601660 pathogenic not provided 2016-10-13 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.