rs34612342

chr1-45332803-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 10P and 4B. PM1 PP5_Very_Strong BS2

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:58 O:4
• Conservation: PhyloP100: 7.26

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]

ACMG classification

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, 15 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
MUTYH	NM_001128425.2	c.536A>G	p.Tyr179Cys	missense_variant	7/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.452A>G	p.Tyr151Cys	missense_variant	7/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.536A>G	p.Tyr179Cys	missense_variant	7/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.452A>G	p.Tyr151Cys	missense_variant	7/16	1	NM_001048174.2	A1

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

GnomAD3 exomes AF: 0.00154 AC: 386 AN: 251454 Hom.: 0 AF XY: 0.00160 AC XY: 218 AN XY: 135912

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

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

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:58 Other:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:26 Other:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2007	- -
Pathogenic, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 29, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	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). 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, no assertion criteria provided	research	deCODE genetics, Amgen	Jul 21, 2023	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. -
Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Mar 26, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Oct 13, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 01, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 26, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 25, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 14, 2023	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. -
not provided, no classification provided	phenotyping only	GenomeConnect, 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 submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 25, 2022	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Nov 30, 2021	ACMG classification criteria: PS3 moderate, PM3 very strong, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 09, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 31, 2022	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. -
not provided, no classification provided	phenotyping only	GenomeConnect - 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Sep 20, 2022	ACMG criteria used to clasify this variant: PS3, PS4, PP3, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Heidelberg University	Apr 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 31, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 19, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Nov 05, 2023	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 -
not provided, no classification provided	literature only	GeneReviews	-	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 -

not provided Pathogenic:19

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MUTYH: PS3, PS4, PP1:Moderate, PP3 -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Aug 20, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 18, 2021	PP1, PP3, PP5, PM3, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 08, 2021	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. -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 11, 2022	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). -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Feb 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 26, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 23, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary cancer-predisposing syndrome Pathogenic:7

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Mar 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 16, 2024	The c.536A>G (p.Y179C) alteration is located in coding exon 7 of the MUTYH gene. This alteration results from a A to G substitution at nucleotide position 536, causing the tyrosine (Y) at amino acid position 179 to be replaced by a cysteine (C). Based on data from gnomAD, the G allele has an overall frequency of 0.154% (435/282806) total alleles studied. The highest observed frequency was 0.25% (323/129154) of European (non-Finnish) alleles. This alteration represents a founder mutation in multiple populations and accounts for a significant proportion of pathogenic MUTYH mutations reported to date (Nielsen, 2009; Aretz, 2014). 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, 2009; Butterworth, 2006). 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, 2010). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	True Health Diagnostics	Dec 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 20, 2023	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 (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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Mar 05, 2024	- -

Carcinoma of colon Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Department 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. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 15, 2022

- -

MUTYH-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 07, 2023

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

Likely pathogenic, no assertion criteria provided

clinical testing

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

Aug 07, 2021

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

Endometrial carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2007

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 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

Other links and lift over

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