ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.536A>G (p.Tyr179Cys) (rs34612342)

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Total submissions: 29
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000079502 SCV000604310 pathogenic not provided 2017-09-18 criteria provided, single submitter clinical testing The MUTYH c.494A>G; p.Tyr165Cys variant (also known as NM_001128425.1: c.536A>G, p.Tyr179Cys) has been well described in the literature as one of the two common MUTYH pathogenic variants. It has been observed in homozygous or compound heterozygous form with other pathogenic MUTYH variants in patients with colorectal cancer, familial adenomatous polyposis (FAP) or attenuated FAP (Aretz 2014). Functional studies have shown that the p.Tyr165Cys variant results in severely decreased DNA binding and adenine DNA glycosylase activity (Al-Tassan 2002, Ali 2008, Goto 2010, Molatore 2010). REFERENCES Ali M et al. Characterization of mutant MUTYH proteins associated with familial colorectal cancer. Gastroenterology. 2008; 135(2):499-507. Al-Tassan N et al. Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors. Nat Genet. 2002; 30(2):227-32. Aretz S et al. MUTYH-associated polyposis (MAP): evidence for the origin of the common European mutations p.Tyr179Cys and p.Gly396Asp by founder events. Eur J Hum Genet. 2014; 22(7):923-9. Goto M et al. Adenine DNA glycosylase activity of 14 human MutY homolog (MUTYH) variant proteins found in patients with colorectal polyposis and cancer. Hum Mutat. 2010; 31(11):E1861-74. Molatore S et al. MUTYH mutations associated with familial adenomatous polyposis: functional characterization by a mammalian cell-based assay. Hum Mutat. 2010; 31(2):159-66.
Ambry Genetics RCV000115766 SCV000185514 pathogenic Hereditary cancer-predisposing syndrome 2018-04-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous,Deficient protein function by in vitro/ex vivo assay,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other strong data supporting pathogenic classification
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000005612 SCV000043377 pathogenic MYH-associated polyposis 2012-07-13 no assertion criteria provided research Converted during submission to Pathogenic.
Center for Human Genetics, Inc RCV000005612 SCV000781798 pathogenic MYH-associated polyposis 2016-11-01 criteria provided, single submitter clinical testing
Color RCV000115766 SCV000537631 pathogenic Hereditary cancer-predisposing syndrome 2015-03-21 criteria provided, single submitter clinical testing
Counsyl RCV000005612 SCV000678191 pathogenic MYH-associated polyposis 2015-05-26 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000005612 SCV000592686 pathogenic MYH-associated polyposis 2015-11-20 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000005612 SCV000257796 pathogenic MYH-associated polyposis 2015-06-25 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000079502 SCV000111384 pathogenic not provided 2017-09-26 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515387 SCV000611286 pathogenic MYH-associated polyposis; Pilomatrixoma; Neoplasm of stomach 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000079502 SCV000149675 pathogenic not provided 2018-08-17 criteria provided, single submitter clinical testing This pathogenic variant is denoted MUTYH c.536A>G at the cDNA level, p.Tyr179Cys (Y179C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAC>TGC). This variant, also known as Tyr165Cys using an alternate reference sequence (NM_001048171.1), has been published in the literature as one of the two common MUTYH missense pathogenic variants in Western populations, and, when found in combination with another pathogenic variant, is known to cause MUTYH-associated polyposis (MAP) (Nielsen 2009, Leoz 2015). Multiple in vitro functional studies demonstrate this variant's pathogenic effect (Ali 2008, Grasso 2014, Komine 2015). MUTYH Tyr179Cys was observed at an allele frequency of 0.24% (310/126,692) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the Pseudo HhH motif and the 8-oxo-G binding domain (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.
GeneKor MSA RCV000115766 SCV000821743 pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
GeneReviews RCV000005612 SCV000057869 pathogenic MYH-associated polyposis 2015-09-24 no assertion criteria provided literature only
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000005612 SCV000993434 likely pathogenic MYH-associated polyposis 2019-03-26 criteria provided, single submitter research
ITMI RCV000121607 SCV000085805 not provided not specified 2013-09-19 no assertion provided reference population
Illumina Clinical Services Laboratory,Illumina RCV000005612 SCV000357903 pathogenic MYH-associated polyposis 2016-06-14 criteria provided, single submitter clinical testing Several studies describe the c.494A>G (p.Tyr165Cys) as a common pathogenic variant, also referred to as c.536A>G (p.Tyr179Cys) in the literature. In 2002, Al-Tassan et al. described a family with three siblings with multiple colorectal adenomas and carcinoma, found to be compound heterozygous for the p.Tyr165Cys variant. Four unaffected siblings were all heterozygous for a single variant or homozygous wild-type. Nielson et al. (2005) identified the p.Tyr165Cys variant in a presumed compound heterozygous state in 13 individuals and in a homozygous state in 14 individuals, out of 170 patients with polyposis who previously tested negative for APC mutations. The p.Tyr165Cys variant was the most common variant identified in the study cohort. Control data are unavailable for the p.Tyr165Cys variant which is reported at a frequency of 0.00302 in the European American population of the Exome Sequencing Project. In 2009, Nielsen et al. assessed genotype phenotype relationships of the common p.Tyr165Cys and p.Gly396Asp variants. Patients homozygous for the p.Tyr165Cys variant had a significantly increased chance of developing colorectal cancer compared to patients homozygous for the p.Gly396Asp variant or compound heterozygous for the p.Tyr165Cys and Gly382Asp variants (Nielsen et al. 2009). Ali et al. (2008) demonstrated significantly impaired DNA glycosylase and binding activities of the p.Tyr165Cys variant via in vitro functional assays, which were unable to generate any detectable cleavage products or to bind to the substrates. Similarly, Goto et al. (2010) demonstrated the adenine DNA glycosylase activity of the p. p.Tyr165Cys protein was 4.5% of wild-type. The collective evidence supports p.Tyr165Cys as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000588997 SCV000697700 pathogenic MUTYH-associated polyposis 2015-11-20 criteria provided, single submitter clinical testing
Invitae RCV000005612 SCV000166454 pathogenic MYH-associated polyposis 2019-01-05 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 179 of the MUTYH protein (p.Tyr179Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is a known common cause of MUTYH-associated polyposis (PMID: 23035301). This variant has been reported to co-segregate with disease in individuals affected with colorectal cancer, familial adenomatous polyposis (FAP), and attenuated FAP (PMID: 12606733, 16557584, 17489848, 19793053, 21063410, 24444654). This variant is also known as c.494A>G (p.Tyr165Cys) in the literature. ClinVar contains an entry for this variant (Variation ID: 5293). MUTYH-related conditions are inherited in an autosomal recessive fashion. However, there is evidence that monoallelic pathogenic MUTYH variants including this particular variant are associated with increased risk of colon cancer (PMID: 16492921, 19394335, 21171015, 24444654). Experimental studies have shown that this missense change disrupts MUTYH protein function (PMID: 11818965, 18534194, 19953527, 20848659). For these reasons, this variant has been classified as Pathogenic.
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000005612 SCV000223938 pathogenic MYH-associated polyposis 2014-10-13 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000005612 SCV000245637 pathogenic MYH-associated polyposis 2015-07-30 criteria provided, single submitter clinical testing The p.Tyr179Cys variant in MUTYH is a well-established pathogenic variant for MU TYH-associated polyposis, segregating with disease in multiple affected individu als (Nielsen 2009, Vogt 2009). This variant has also been reported by other clin ical laboratories in ClinVar (Variation ID 5293) and been identified in 0.2% (31 0/126692) of European chromosomes by the Genome Aggregation Database (gnomAD, ht tp://gnomad.broadinstitute.org; dbSNP rs34612342). Although this variant has bee n seen in the general population, its frequency is low enough to be consistent w ith a recessive carrier frequency. Functional studies indicate this variant affe cts MUTYH enzyme activity (Kundu 2009, Molatore 2009). In summary, this variant meets criteria to be classified as pathogenic for MUTYH-associated polyposis in an autosomal recessive manner based upon presence in multiple affected individua ls, segregation and functional studies. ACMG/AMP Criteria applied: PM3_VeryStron g, PP1_strong, PS3_supporting.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000079502 SCV000691950 pathogenic not provided no assertion criteria provided clinical testing
Mendelics RCV000005612 SCV000837775 pathogenic MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
OMIM RCV000005612 SCV000025794 pathogenic MYH-associated polyposis 2007-12-01 no assertion criteria provided literature only
OMIM RCV000005613 SCV000025795 pathogenic Endometrial carcinoma 2007-12-01 no assertion criteria provided literature only
Pathway Genomics RCV000144631 SCV000189958 pathogenic Carcinoma of colon 2014-07-24 no assertion criteria provided clinical testing
PreventionGenetics RCV000079502 SCV000806361 pathogenic not provided 2016-01-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000079502 SCV000601651 pathogenic not provided 2016-09-02 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000115766 SCV000788070 pathogenic Hereditary cancer-predisposing syndrome 2017-12-08 no assertion criteria provided clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000115766 SCV000266097 pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing

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