Menu
GeneBe

rs34612342

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 10P and 4B. PM1PP5_Very_StrongBS2

The NM_001048174.2(MUTYH):c.452A>G(p.Tyr151Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,614,184 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y151Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0016 ( 2 hom., cov: 33)
Exomes 𝑓: 0.0020 ( 3 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

11
4
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:55O:4

Conservation

PhyloP100: 7.26
Variant links:
Genes affected
MUTYH (HGNC:7527): (mutY DNA glycosylase) This gene encodes a DNA glycosylase involved in oxidative DNA damage repair. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a major oxidatively damaged DNA lesion. The protein is localized to the nucleus and mitochondria. This gene product is thought to play a role in signaling apoptosis by the introduction of single-strand breaks following oxidative damage. Mutations in this gene result in heritable predisposition to colorectal cancer, termed MUTYH-associated polyposis (MAP). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_001048174.2
PP5
Variant 1-45332803-T-C is Pathogenic according to our data. Variant chr1-45332803-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45332803-T-C is described in Lovd as [Pathogenic]. Variant chr1-45332803-T-C is described in Lovd as [Pathogenic]. Variant chr1-45332803-T-C is described in Lovd as [Pathogenic].
BS2
High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MUTYHNM_001128425.2 linkuse as main transcriptc.536A>G p.Tyr179Cys missense_variant 7/16 ENST00000710952.2
MUTYHNM_001048174.2 linkuse as main transcriptc.452A>G p.Tyr151Cys missense_variant 7/16 ENST00000456914.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MUTYHENST00000710952.2 linkuse as main transcriptc.536A>G p.Tyr179Cys missense_variant 7/16 NM_001128425.2
MUTYHENST00000456914.7 linkuse as main transcriptc.452A>G p.Tyr151Cys missense_variant 7/161 NM_001048174.2 A1Q9UIF7-6

Frequencies

GnomAD3 genomes
AF:
0.00156
AC:
238
AN:
152182
Hom.:
2
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000435
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00268
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00141
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00232
Gnomad OTH
AF:
0.00287
GnomAD3 exomes
AF:
0.00154
AC:
386
AN:
251454
Hom.:
0
AF XY:
0.00160
AC XY:
218
AN XY:
135912
show subpopulations
Gnomad AFR exome
AF:
0.000493
Gnomad AMR exome
AF:
0.00121
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00152
Gnomad NFE exome
AF:
0.00254
Gnomad OTH exome
AF:
0.00212
GnomAD4 exome
AF:
0.00196
AC:
2864
AN:
1461884
Hom.:
3
Cov.:
36
AF XY:
0.00191
AC XY:
1388
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.000209
Gnomad4 AMR exome
AF:
0.00114
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00165
Gnomad4 NFE exome
AF:
0.00233
Gnomad4 OTH exome
AF:
0.00197
GnomAD4 genome
AF:
0.00156
AC:
238
AN:
152300
Hom.:
2
Cov.:
33
AF XY:
0.00148
AC XY:
110
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.000433
Gnomad4 AMR
AF:
0.00268
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00141
Gnomad4 NFE
AF:
0.00232
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.00200
Hom.:
2
Bravo
AF:
0.00135
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.00130
AC:
5
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00302
AC:
26
ExAC
AF:
0.00162
AC:
197
EpiCase
AF:
0.00174
EpiControl
AF:
0.00184

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:55Other:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:24Other:3
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterJul 29, 2022- -
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 2007- -
not provided, no classification providedphenotyping onlyGenomeConnect, ClinGen-Variant interpreted as Pathogenic and reported on 07-22-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityFeb 09, 2022- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 14, 2023Variant summary: MUTYH c.536A>G (p.Tyr179Cys) results in a non-conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 251454 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.0015 vs 0.0046), allowing no conclusion about variant significance. c.536A>G has been reported in the literature in many individuals affected with MUTYH-Associated Polyposis (e.g., Kanter-Smoler, Nielsen_2005). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant causes loss of protein function, resulting in defective DNA-binding and glycosylase activities (e.g., Komine_2015, Ali_2008). 38 ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria providedclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityOct 13, 2014- -
Pathogenic, criteria provided, single submitterclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaJun 25, 2015- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsJul 02, 2018- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsOct 31, 2023- -
Pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinNov 30, 2021ACMG classification criteria: PS3 moderate, PM3 very strong, PP1 -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, Heidelberg UniversityApr 28, 2023- -
Pathogenic, no assertion criteria providedresearchdeCODE genetics, AmgenJul 21, 2023The variant NM_001048174.2:c.452A>G (chr1:45332803) in MUTYH was detected in 236 heterozygotes and 2 homozygotes out of 58K WGS Icelanders (MAF= 0,2%). Following imputation in a set of 166K Icelanders (658 heterozygotes and 2 homozygotes) we observed an association with colorectal cancer under a recessive model using 4991 cases and 314812 controls (OR= 60.78, P= 3.57e-03). This variant has been reported in ClinVar previously as pathogenic/likely pathogenic. Based on ACMG criteria (PS3, PS4, PM2, PP5) this variant classifies as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingHuman Genetics Bochum, Ruhr University BochumSep 20, 2022ACMG criteria used to clasify this variant: PS3, PS4, PP3, PP1 -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJul 30, 2015The 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. -
Likely pathogenic, criteria provided, single submitterresearchHudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for BiotechnologyMar 26, 2019- -
Pathogenic, no assertion criteria providedclinical testingGenomics England Pilot Project, Genomics England-- -
Pathogenic, no assertion criteria providedresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJul 13, 2012- -
Pathogenic, criteria provided, single submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalAug 31, 2022The MUTYH c.536A>G (p.Tyr179Cys) is a well-established pathogenic founder mutation for MUTYH-associated polyposis in the European population (PMID: 23035301, 23361220). 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: 11818965, 12606733, 16557584, 19032956, 19732775, 27829682). Although MUTYH-associated polyposis is typically caused by biallelic variants affecting the MUTYH gene, there is evidence that monoallelic pathogenic MUTYH variants including this particular variant are associated with increased risk of colon cancer (PMID: 16492921, 19394335, 21063410, 24444654). This variant has a maximum subpopulation frequency of 0.25% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, and functional studies have shown that this missense change disrupts MUTYH protein function (PMID: 18534194, 19836313, 19953527, 20418187, 20848659, 22926731, 23108399, 24569162, 25820570). This variant is also known as p.Tyr165Cys in the literature. In summary, this variant meets criteria to be classified as pathogenic. -
not provided, no classification providedliterature onlyGeneReviews-Common pathogenic variants carried by approximately 1%-2% of the general population that account for ≥90% of all MUTYH pathogenic variants in northern European populations; ≤70% of persons with MUTYH-Associated Polyposis (MAP) harbor at least 1 of these variants, 536A>G or 1187G>A -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 31, 2024This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 179 of the MUTYH protein (p.Tyr179Cys). This variant is present in population databases (rs34612342, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. 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). 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). This variant is also known as c.494A>G (p.Tyr165Cys). ClinVar contains an entry for this variant (Variation ID: 5293). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MUTYH function (PMID: 11818965, 18534194, 19953527, 20848659). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJan 25, 2022This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitterclinical testingGenetics and Molecular Pathology, SA PathologyApr 19, 2022The heterozygous variant c.536A>G detected in exon 7 of the MUTYH gene is a missense change resulting in an amino acid substitution from a Tyrosine to a Cysteine at codon 179, p.(Tyr179Cys). This variant has been reported multiple times in both LOVD and ClinVar databases as pathogenic. This variant is one of the common MUTYH pathogenic founder mutations in European populations, which has been reported to co-segregate with colorectal cancer and MUTYH-associated polyposis (MAP) (Aretz et al, Eur J Hum Genet (2014) 22(7):923-9 and Theodoratou et al, British Journal of Cancer (2010) 103(12):1875-84). In populations of European origin, the missense variants p.(Tyr179Cys) and p.(Gly396Asp) account for up to 80% of MUTYH variants identified in MAP patients (Sieber et al, N Engl J Med (2003) 348(9):791-9; Kanter-Smoler et al, Clin Gastroenterol Hepatol (2006) 4(4):499-506 and Aretz et al, Eur J Hum Genet (2014) 22(7):923-9). In healthy controls from different populations, the allele frequencies for this variant range from 0.04 to 0.4% (Aretz et al, Eur J Hum Genet (2014) 22(7):923-9). Functional studies have shown that this missense change disrupts MUTYH protein function (Parker et al, Carcinogenesis, (2005) 26(11):2010-18; Mohsin et al, Gastroentorology (2008) 135(2):499-507 and Ruggieri et al, Oncogene (2013) 32(38):4500-8). Based on current knowledge, this is a pathogenic (Class 5) variant. This patient is a heterozygous carrier of a recessive condition. -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016Several 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. -
Pathogenic, criteria provided, single submitterclinical testingDepartment of Molecular Diagnostics, Institute of Oncology LjubljanaApr 02, 2020- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Human Genetics, Inc, Center for Human Genetics, IncNov 01, 2016- -
Pathogenic, criteria provided, single submitterclinical testingCounsylMay 26, 2015- -
not provided, no classification providedphenotyping onlyGenomeConnect - Invitae Patient Insights Network-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. -
not provided Pathogenic:19
Pathogenic, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJan 11, 2022DNA sequence analysis of the MUTYH gene demonstrated a sequence change, c.536A>G, in exon 7 that results in an amino acid change, p.Tyr179Cys. This pathogenic sequence change is a known founder mutation in the European population and has been described in the gnomAD database with a frequency of 0.25% in the non-Finnish European population (dbSNP rs34612342). This pathogenic sequence change has previously been described in the homozygous or compound heterozygous state in multiple patients with MUTYH-associated polyposis (PMIDs: 19032956, 11818965; Cleary et al., 2009). Multiple in vitro studies have supported the pathogenic nature of the p.Tyr179Cys change (PMIDs: 24569162, 25820570). The p.Tyr179Cys change affects a highly conserved amino acid residue located in a domain of the MUTYH protein that is known to be functional. The p.Tyr179Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). -
Pathogenic, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenNov 03, 2021- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2024MUTYH: PS3, PS4, PP1:Moderate, PP3 -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMar 18, 2021PP1, PP3, PP5, PM3, PVS1 -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Sep 26, 2017- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 26, 2021One of two common MUTYH pathogenic variants which together account for up to 80% of pathogenic MUTYH variants (Cleary 2009); Observed in the homozygous and compound heterozygous state in multiple individuals with MUTYH-Associated Polyposis (Nielsen 2009, de Leon 2017, DeRycke 2017, Furlan 2017); Published functional studies demonstrate a damaging effect: reduced glycosylase and DNA binding activity (Ali 2008, Goto 2010, Komine 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.Tyr165Cys; This variant is associated with the following publications: (PMID: 21178863, 19998059, 19032956, 20418187, 19836313, 20571908, 19300419, 22744763, 27153395, 25980754, 27705013, 28944238, 28141798, 20848659, 30256826, 30609409, 29506128, 22703879, 21063410, 22926731, 23361220, 18534194, 19732775, 19953527, 24733792, 23108399, 24728327, 25931827, 24569162, 11818965, 12606733, 17489848, 19793053, 16557584, 24444654, 16492921, 19394335, 21171015, 17039270, 27498913, 25820570, 27829682, 27631816, 27978560, 26446593, 27797849, 26681312, 26202870, 28709830, 28873162, 28503720, 27696107, 27799157, 27783336, 28591191, 29557500, 26517685, 26556299, 30953464, 30067863, 30564557, 30582135, 30604180, 30833417, 31159747, 30676620, 30877237, 31921681, 30306255, 32088803, 30291343, 31447099, 31263571, 32283892, 31980526, 23035301, 34026625, 34426522, 34259353, 31589614, 33193653, 33384714, 32338768, 33258288, 32615015, 32830346, 33504652, 33332384, 30613976, 33442023) -
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalFeb 06, 2024- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalAug 20, 2015- -
Pathogenic, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsFeb 02, 2022- -
Pathogenic, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesAug 23, 2023The MUTYH c.536A>G; p.Tyr179Cys variant (rs34612342), also known as p.Tyr165Cys NM_001048171.1, 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). This variant is also report in ClinVar (Variation ID: 5293) and is found in the general population with an overall allele frequency of 0.1538% (435/282,806 alleles) in the Genome Aggregation Database. 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). Computational analyses predict that this variant is deleterious (REVEL: 0.963). 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. PMID:18534194. 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. PMID:11818965. 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. PMID:23361220. 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. PMID:20848659. 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. PMID:19953527. -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoMar 08, 2021In the published literature, this variant has been reported in multiple individuals affected with MUTYH-associated polyposis (MAP), and is reported to be one of two pathogenic variants associated with MAP in individuals of European ancestry (PMIDs: 12606733 (2003), 17489848 (2007), 19793053 (2009), 23361220 (2014)). In addition, this variant has been reported as having a deleterious effect on MUTYH protein function (PMIDs: 24569162 (2014), 20418187 (2010), 19836313 (2009), 19032956 (2009)). Based on the available information, this variant is classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:6
Pathogenic, criteria provided, single submitterclinical testingUniversity of Washington Department of Laboratory Medicine, University of WashingtonNov 20, 2015- -
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsApr 19, 2022The 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. -
Pathogenic, criteria provided, single submittercurationSema4, Sema4Mar 07, 2022- -
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthFeb 20, 2023This missense variant replaces tyrosine with cysteine at codon 179 of the MUTYH protein. This variant is also known as 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 >= 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. -
Pathogenic, no assertion criteria providedclinical testingTrue Health DiagnosticsDec 08, 2017- -
Pathogenic, criteria provided, single submitterclinical testingGeneKor MSAJan 01, 2020This 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). -
Carcinoma of colon Pathogenic:2
Pathogenic, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-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. -
Pathogenic, no assertion criteria providedclinical testingPathway GenomicsJul 24, 2014- -
MUTYH-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesNov 07, 2023The MUTYH c.536A>G variant is predicted to result in the amino acid substitution p.Tyr179Cys. This variant, also described as p.Tyr165Cys in the literature (Poulsen and Bisgaard. 2008. PubMed ID: 19506731), is among the most common contributors to autosomal recessive MUTYH-associated polyposis (http://www.ncbi.nlm.nih.gov/books/NBK107219/) and has been shown to co-segregate with disease in multiple patients with colorectal cancer, familial adenomatous polyposis (FAP), and attenuated FAP (Sieber et al. 2003. PubMed ID: 12606733; Aretz et al. 2006. PubMed ID: 16557584; Theodoratou et al. 2010. PubMed ID: 21063410). This variant has also been observed in individuals with breast cancers with and without a family history of cancers (Wasielewski et al. 2010. PubMed ID: 20191381; Rennert et al. 2012. PubMed ID: 21952991). Several studies have shown that the p.Tyr179Cys variant disrupts MUTYH protein function (Ali et al. 2008. PubMed ID: 18534194; Molatore et al. 2010. PubMed ID: 19953527). In ClinVar, it is documented as a likely pathogenic/pathogenic variant (https://www.ncbi.nlm.nih.gov/clinvar/variation/5293/). Based on these data, we interpret this variant as pathogenic. -
Gastric cancer;C3272841:Familial adenomatous polyposis 2 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 15, 2022- -
Gastric cancer Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingMedical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health SciencesAug 07, 2021Invasive Ductal Carcinoma Estrogen Receptor: Negative Progesterone Receptor: Negative HER2 Receptor: Positive -
Endometrial carcinoma Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 2007- -
not specified Other:1
not provided, no classification providedreference populationITMISep 19, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.83
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Pathogenic
0.43
Cadd
Uncertain
26
Dann
Uncertain
1.0
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.99
D
M_CAP
Pathogenic
0.33
D
MetaRNN
Uncertain
0.54
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationTaster
Benign
1.0
A;A;A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-8.6
D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
.;.;.;.;.;D;D;.;D;.;.;.
Vest4
0.99
MVP
0.98
MPC
0.62
ClinPred
0.45
T
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.99
gMVP
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs34612342; hg19: chr1-45798475; COSMIC: COSV58344606; COSMIC: COSV58344606; API