rs34612342
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PP5_Very_Strong
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 (★★).
Frequency
Genomes: 𝑓 0.0016 ( 2 hom., cov: 33)
Exomes 𝑓: 0.0020 ( 3 hom. )
Consequence
MUTYH
NM_001048174.2 missense
NM_001048174.2 missense
Scores
13
5
1
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM1
In a helix (size 13) in uniprot entity MUTYH_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MUTYH | NM_001128425.2 | c.536A>G | p.Tyr179Cys | missense_variant | 7/16 | ENST00000710952.2 | NP_001121897.1 | |
| MUTYH | NM_001048174.2 | c.452A>G | p.Tyr151Cys | missense_variant | 7/16 | ENST00000456914.7 | NP_001041639.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MUTYH | ENST00000710952.2 | c.536A>G | p.Tyr179Cys | missense_variant | 7/16 | NM_001128425.2 | ENSP00000518552 | |||
| MUTYH | ENST00000456914.7 | c.452A>G | p.Tyr151Cys | missense_variant | 7/16 | 1 | NM_001048174.2 | ENSP00000407590 | A1 |
Frequencies
GnomAD3 genomes 0.00156 AC: 238AN: 152182Hom.: 2 Cov.: 33
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GnomAD3 exomes AF: 0.00154 AC: 386AN: 251454Hom.: 0 AF XY: 0.00160 AC XY: 218AN XY: 135912
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:59Other:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial adenomatous polyposis 2 Pathogenic:26Other:3
| 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]. - |
| Likely pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Mar 26, 2019 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2007 | - - |
| 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 | Labcorp Genetics (formerly Invitae), Labcorp | 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, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
| 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 | 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, no assertion criteria provided | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Oct 13, 2014 | - - |
| 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 | Revvity Omics, Revvity | Feb 09, 2022 | - - |
| 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 - |
| 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 | Institute of Human Genetics, Heidelberg University | Apr 28, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
| 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 | Mendelics | Jul 02, 2018 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jul 29, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 29, 2024 | - - |
| 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 | 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 | 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 | 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. - |
| 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 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 26, 2015 | - - |
| 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. - |
| 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 Pathogenic:20
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Aug 20, 2015 | - - |
| 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 | 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, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 18, 2021 | PP1, PP3, PP5, PM3, PVS1 - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| 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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| 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, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Feb 02, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | MUTYH: PS3, PS4, PP1:Moderate, PP3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 26, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Feb 26, 2024 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:7
| 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. - |
| 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 | 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Mar 05, 2024 | - - |
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 07, 2022 | - - |
Carcinoma of colon Pathogenic:2
| 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
Gastric cancer;C3272841:Familial adenomatous polyposis 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 15, 2022 | - - |
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 - |
MUTYH-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 07, 2024 | 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. - |
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
.;.;.;.;.;D;.;.;.;D;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;D;.;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;.;.;.;H;.;.;.;.;.;.
MutationTaster
Benign
A;A;A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
.;.;.;.;.;D;D;.;D;.;.;.
Vest4
MVP
MPC
0.62
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at