ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.452A>G (p.Tyr151Cys) (rs34612342)

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Total submissions: 39
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000079502 SCV000111384 pathogenic not provided 2017-09-26 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.
Invitae RCV000005612 SCV000166454 pathogenic MYH-associated polyposis 2020-11-02 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 and polyposis (with polyp numbers ranging from 10 to >100) (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.
Ambry Genetics RCV000115766 SCV000185514 pathogenic Hereditary cancer-predisposing syndrome 2019-04-17 criteria provided, single submitter clinical testing The p.Y179C pathogenic mutation (also known as c.536A>G and p.Y165C) is located in coding exon 7 of the MUTYH gene. This alteration represents a founder mutation in multiple populations and accounts for a significant proportion of pathogenic MUTYH mutations reported to date (Nielsen M et al. Gastroenterology. 2009 Feb;136:471-6; Aretz S et al. Eur. J. Hum. Genet. 2014 Jul;22(7):923-9). A 2-fold increased risk of colorectal cancer (CRC) risk for carriers of a single (mono-allelic) MUTYH mutation has been reported as similar to the CRC risk of those with an affected first degree relative (Jones N et al. Gastroenterology. 2009 Aug;137:489-94; Butterworth AS et al. Eur. J. Cancer. 2006 Jan;42:216-27). A large scale meta-analysis to refine CRC risk estimates associated with MUTYH variants, including more than 20000 cases and 15000 controls, demonstrated an approximately 1.5 fold increase in CRC risk for carriers of the p.Y179C mutation (Theodoratou E et al. Br. J. Cancer. 2010 Dec;103:1875-84). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as a pathogenic mutation.
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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000005612 SCV000257796 pathogenic MYH-associated polyposis 2015-06-25 criteria provided, single submitter 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
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.
Color Health, Inc RCV000115766 SCV000537631 pathogenic Hereditary cancer-predisposing syndrome 2021-02-11 criteria provided, single submitter clinical testing This missense variant replaces tyrosine with cysteine at codon 179 of the MUTYH protein. This variant is also known p.Tyr165Cys (c.494A>G) based on an alternate transcript NM_001048171. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold ‚â•0.7, PMID: 27666373). Functional studies have shown that the mutant protein is defective in DNA binding and repair, and glycosylase activity (PMID: 18534194, 19953527). This variant is a well-established pathogenic variant known to cause adenomatous polyposis and colorectal cancer in homozygous and compound heterozygous individuals (PMID: 11818965, 12606733, 16338133, 16492921, 16557584, 17489848, 18534194, 19032956, 19394335, 19793053, 20418187, 21063410, 21171015, 22266422, 23361220, 24444654, 27829682). This variant is one of two most common pathogenic MUTYH variants, which together account for up to 80% of MUTYH-associated disease observed in Caucasian individuals (PMID: 29147111). This variant has been identified in 435/282806 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000079502 SCV000601651 pathogenic not provided 2016-09-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282789 SCV000604310 pathogenic none provided 2020-08-07 criteria provided, single submitter clinical testing The MUTYH c.536A>G; p.Tyr179Cys variant (rs34612342; also known as NM_001048171: c.494A>G; p.Tyr165Cys) 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.Tyr179Cys variant results in severely decreased DNA binding and adenine DNA glycosylase activity (Al-Tassan 2002, Ali 2008, Goto 2010, Molatore 2010). Based on available information, this variant is considered to be pathogenic. 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.
Fulgent Genetics,Fulgent Genetics RCV000515387 SCV000611286 pathogenic MYH-associated polyposis; Pilomatrixoma; Neoplasm of stomach 2017-05-18 criteria provided, single submitter clinical testing
Counsyl RCV000005612 SCV000678191 pathogenic MYH-associated polyposis 2015-05-26 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000079502 SCV000691950 pathogenic not provided 2021-03-18 criteria provided, single submitter clinical testing PVS1, PM3, PP1, PP3, PP5
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000005612 SCV000697700 pathogenic MYH-associated polyposis 2015-11-20 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000005612 SCV000781798 pathogenic MYH-associated polyposis 2016-11-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000079502 SCV000806361 pathogenic not provided 2016-01-06 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115766 SCV000821743 pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 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 (Grantham Score 194).This variant, also known as Y165C using an alternative reference sequence, has been published in the literature as one of the two common MUTYH missense mutations in Western populations, and, when found in combination with another pathogenic variant, is known to cause MUTYH-associated polyposis (MAP) (PMID: 19032956). It has been reported to co-segregate with disease in individuals affected with colorectal cancer, familial adenomatous polyposis (FAP), and attenuated FAP (PMID: 24444654; 21063410 ; 19793053 ; 17489848, 31159747) Experimental studies have shown that this variant disrupts MUTYH protein function (PMID: 20848659 ; 19953527 ; 11818965 ). The mutation database ClinVar contains entries for this variant (Variation ID:5293).
Mendelics RCV000005612 SCV000837775 pathogenic MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000005612 SCV000993434 likely pathogenic MYH-associated polyposis 2019-03-26 criteria provided, single submitter research
CeGaT Praxis fuer Humangenetik Tuebingen RCV000079502 SCV001248085 pathogenic not provided 2021-04-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000079502 SCV001447259 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000079502 SCV001450299 pathogenic not provided 2015-08-20 criteria provided, single submitter clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000005612 SCV001499743 pathogenic MYH-associated polyposis 2020-04-02 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
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.
GeneReviews RCV000005612 SCV000057869 pathogenic MYH-associated polyposis 2019-10-08 no assertion criteria provided literature only
ITMI RCV000121607 SCV000085805 not provided not specified 2013-09-19 no assertion provided reference population
Pathway Genomics RCV000144631 SCV000189958 pathogenic Carcinoma of colon 2014-07-24 no assertion criteria provided clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000005612 SCV000223938 pathogenic MYH-associated polyposis 2014-10-13 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000144631 SCV000592686 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The MUTYH p.Tyr179Cys variant was identified in 878 of 42,504 proband chromosomes (frequency: 0.03) from individuals or families with MAP or colorectal cancer (CRC). Of these 292 were heterozygous carriers, 99 were homozygous and 487 were compound heterozygotes. The variant was present in 156 of 31,262 control chromosomes (frequency: 0.005) from healthy individuals (Al-Tassan 2002, Nielsen 2009, Nascimbeni 2010, Theodoratou 2010, Vogt 2009, Sieber 2003). The variant was also identified in dbSNP (ID: rs34612342) as With Pathogenic allele, ClinVar (classified as pathogenic by GeneDx, Invitae, Ambry Genetics, Color Genomics, Pathway Genomics and more), Clinvitae (classified as pathogenic by ClinVar and Invitae), Cosmic (pathogenic), and in Insight Colon Cancer Gene Variant Database (535x pathogenic). The variant was not identified in MutDB, or UMD-LSDB databases. The variant was identified in control databases in 412 of 277178 chromosomes at a frequency of 0.001486 (Genome Aggregation Consortium Feb 27, 2017). The p.Tyr179 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In a meta-analysis study (Theodoratou 2010), to assess and refine CRC risk estimates associated with bi-allelic and mono-allelic MUTYH variants, MUTYH bi-allelic carriers demonstrated a 28-fold increase in CRC risk. Significant bi-allelic effects were also observed for G396D and Y179C/G396D compound heterozygotes and a marginal mono-allelic effect for variant Y179C. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
True Health Diagnostics RCV000115766 SCV000788070 pathogenic Hereditary cancer-predisposing syndrome 2017-12-08 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000079502 SCV001739761 pathogenic not provided no assertion criteria provided clinical testing
GenomeConnect - Invitae Patient Insights Network RCV000005612 SCV001749490 not provided MYH-associated polyposis no assertion provided phenotyping only Variant reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 3/24/2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Genomics England Pilot Project,Genomics England RCV000005612 SCV001760036 pathogenic MYH-associated polyposis no assertion criteria provided clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital,University of Health Sciences RCV001554314 SCV001774805 likely pathogenic Stomach cancer 2021-08-07 no assertion criteria provided clinical testing Invasive Ductal Carcinoma Estrogen Receptor: Negative Progesterone Receptor: Negative HER2 Receptor: Positive
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000079502 SCV001797531 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000079502 SCV001807834 pathogenic not provided no assertion criteria provided clinical testing

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