1-45332803-T-C

Variant names:

• chr1-45332803-T-C
• rs34612342
• NM_001048174.2:c.452A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM1 PP5_Very_Strong BS2_Supporting

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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:61 O:4
• Conservation: PhyloP100: 7.26
• Publications: 399 publications found

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]

MUTYH Gene-Disease associations (from GenCC):

• familial adenomatous polyposis 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
• colorectal cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000288208 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 47 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 5293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.452A>G	p.Tyr151Cys	missense_variant	Exon 7 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.452A>G	p.Tyr151Cys	missense_variant	Exon 7 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1040A>G		non_coding_transcript_exon_variant	Exon 11 of 21			ENSP00000499896.1

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 238 AN: 152182 Hom.: 2 Cov.: 33

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

GnomAD2 exomes AF: 0.00154 AC: 386 AN: 251454 AF XY: 0.00160

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 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

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.00114 AC: 51 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00165 AC: 88 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00233 AC: 2594 AN: 1112008

Other (OTH) AF: 0.00197 AC: 119 AN: 60396

GnomAD4 genome AF: 0.00156 AC: 238 AN: 152300 Hom.: 2 Cov.: 33 AF XY: 0.00148 AC XY: 110 AN XY: 74476

African (AFR) AF: 0.000433 AC: 18 AN: 41544

American (AMR) AF: 0.00268 AC: 41 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00232 AC: 158 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00181 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:61 Other:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:27 Other:3

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Apr 19, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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. -

Dec 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 25, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 20, 2022

Human Genetics Bochum, Ruhr University Bochum

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG criteria used to clasify this variant: PS3, PS4, PP3, PP1 -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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). It has been reported to co-segregate in an autosomal recessive manner 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). 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. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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 -

Jul 29, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 13, 2014

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 21, 2023

deCODE genetics, Amgen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The 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. -

Aug 31, 2022

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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. -

Jul 02, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Apr 28, 2023

Institute of Human Genetics, Heidelberg University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 14, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant 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. -

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GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: 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. -

Jan 25, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Nov 30, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 moderate, PM3 very strong, PP1 -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

May 26, 2015

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Tyr179Cys variant in MUTYH is a well-established pathogenic variant for MUTYH-associated polyposis, segregating with disease in multiple affected individuals (Al-Tassan 2002 PMID: 11818965, Nielsen 2009 PMID: 19032956, Vogt 2009 PMID: 19732775). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 5293) and been identified in 0.2% (323/129154) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs34612342). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Functional studies indicate this variant affects MUTYH enzyme activity (Al-Tassan 2002 PMID: 11818965, Parker 2005 PMID: 15987719, Kundu 2009 PMID: 19836313, Molatore 2009 PMID: 19953527, Grasso 2014 PMID: 24569162). 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 individuals, segregation and functional studies. The ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PS3_Moderate. -

-

Genomics England Pilot Project, Genomics England

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.536A>G (p.Tyr179Cys) variant in the MUTYH gene is located on the exon 7 of the MUTYH gene and is predicted to replace tyrosine with cysteine at codon 179 of the MUTYH protein. This variant has been observed in homozygous or compound heterozygous state in multiple individuals with MUTYH-associated polyposis and colorectal cancer (PMID: 11818965, 12606733, 16338133, 16492921, 16557584, 17489848, 18534194, 19032956, 19394335, 19793053, 20418187, 21063410, 21171015, 22266422, 23361220, 24444654, 27829682). This variant has been reported to co-segregate with disease in multiple individuals (PMID: 12606733, 16557584, 17489848, 19793053, 21063410, 24444654). Functional studies have shown that the mutant protein is defective in DNA binding and repair, and glycosylase activity (PMID:11818965, 18534194, 19953527, 20848659). This missense change has been identified in 435/282806 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (REVEL score %3D 0.963). Based on these evidence, the c.536A>G(p.Tyr179Cys) variant in the MUTYH gene is classified as pathogenic. This finding is consistent with an asymptomatic carrier status of familial adenomatous polyposis in this individual, provided there are no deleterious alterations of the remaining MUTYH allele. -

Mar 26, 2019

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 09, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 05, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in MUTYH is predicted to replace tyrosine with cysteine at codon 151, p.(Tyr151Cys). This variant has been reported as Y179C and Y165C in literature. The tyrosine residue is highly conserved (100 vertebrates, UCSC), and is located in the nudix hydrolase domain. There is a large physicochemical difference between tyrosine and cysteine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.23% (323/129,154 alleles) in the European non-Finnish population. This variant is one of the common European founder variants and has been reported in multiple affected individuals with MUTYH-associated polyposis (PMID: 23361220; 11818965; 37469678; 35218514). The reported individuals were either homozygous or compound heterozygous for the variant. The variant has been reported to segregate in multiple affected individuals with MUTYH-associated polyposis and colorectal cancer from unrelated families (PMID: 23361220; 11818965). An in vitro functional assay showed decreased DNA glycosylase activity in the mutant vector indicating that this variant impacts protein function (PMID: 20848659). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.963). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong; PP1_Strong; PP3_Moderate; PS3_Supporting -

Jun 20, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:20

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 26, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MUTYH: PS3, PS4, PM3, PP1:Moderate, PM2:Supporting, PP3 -

Dec 08, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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. -

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 11, 2022

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA 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). -

Feb 26, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 20, 2015

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 10, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PP4, PM3_very_strong, PS3_supporting, PS4_moderate -

Feb 26, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

One 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) -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Mar 08, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In 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. -

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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Feb 02, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Hereditary cancer-predisposing syndrome Pathogenic:7

Nov 20, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Dec 08, 2017

True Health Diagnostics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). -

Apr 21, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). One study aimed at determining whether MUTYH heterozygosity is associated with increased cancer risk, identified no significant difference in the prevalence of monoallelic MUTYH pathogenic variant (including the p.Y179C founder mutation) carriers from large cohorts of colorectal, endometrial, and breast cancer cases when compared to controls (Thompson AB et al. Fam Cancer, 2022 Oct;21:415-422). 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. -

Mar 07, 2022

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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Mar 05, 2024

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Feb 24, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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. 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. -

Carcinoma of colon Pathogenic:2

Jul 24, 2014

Pathway Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

Gastric cancer;C3272841:Familial adenomatous polyposis 2 Pathogenic:1

Mar 15, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Inherited polyposis and early onset colorectal cancer - germline testing Pathogenic:1

Sep 18, 2024

Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3_Supporting,PM3_Very Strong,PP3 -

MUTYH-related disorder Pathogenic:1

May 07, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The 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 Pathogenic:1

Aug 07, 2021

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Invasive Ductal Carcinoma Estrogen Receptor: Negative Progesterone Receptor: Negative HER2 Receptor: Positive -

Endometrial carcinoma Pathogenic:1

Dec 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

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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
DEOGEN2	Uncertain	0.65	.;.;.;.;.;D;.;.;.;D;.;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;D;.;D;D;D;D;D;D;D;D;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
MutationAssessor	Pathogenic	4.5	.;.;.;.;.;H;.;.;.;.;.;.
PhyloP100		7.3
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
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

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