rs34126013

Variant names:

• chr1-45332458-G-A
• rs34126013
• NM_001048174.2:c.637C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-45332458-G-A
• chr1-45332458-G-C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM5 PP3_Moderate PP5_Very_Strong

The NM_001048174.2(MUTYH):​c.637C>T​(p.Arg213Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000235 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R213Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 6.13
• Publications: 40 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: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 34 uncertain in NM_001048174.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-45332457-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 406867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909
• PP5: Variant 1-45332458-G-A is Pathogenic according to our data. Variant chr1-45332458-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 185274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.637C>T	p.Arg213Trp	missense_variant	Exon 9 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.637C>T	p.Arg213Trp	missense_variant	Exon 9 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1225C>T		non_coding_transcript_exon_variant	Exon 13 of 21			ENSP00000499896.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000679 AC: 17 AN: 250364 AF XY: 0.0000590

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000619

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461758 Hom.: 0 Cov.: 36 AF XY: 0.0000234 AC XY: 17 AN XY: 727174

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 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: 0.000220 AC: 19 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5196

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.0000247 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Jun 16, 2015

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MUTYH: PM3:Strong, PS3, PM2, PP3 -

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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.Arg241Trp variant was identified in 2 of 822 proband chromosomes from individuals with colorectal adenomas (Isidro 2004, Fleischmann 2004). In both cases the variant occurred as a biallelic mutation in combination with the pathogenic MUTYH p.Gly382Asp mutation. The p.Arg241Trp variant was also identified in dbSNP (ID: rs34126013), HGMD, UMD (4X as a causal variant), and the “InSiGHT Colon Cancer Database”. The p.Arg241 residue is conserved across mammals and more distantly related organisms and 5/5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Arg241Trp variant may impact the protein. In addition, one functional study found the variant to be severely defective in A/8-oxoG binding and glycosylase activities, and it failed to complement MutY-deficiency in E.coli (Bai 2005). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Oct 05, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MUTYH c.721C>T (p.Arg241Trp) variant has been reported in the published literature in the compound heterozygous or homozygous state in multiple individuals with polyposis and/or colorectal cancer (PMID: 28533537 (2017), 27194394 (2016), 24470512 (2014), 23561487 (2013), 15366000 (2004)). It has also been reported in individuals with prostate cancer (PMID: 32338768 (2020)) and breast cancer (PMIDs: 30564557 (2018) and 33313162 (2020)), as well as in a breast cancer case and control individuals in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MUTYH)). Experimental studies indicate that the variant is damaging to MUTYH protein function (PMIDs: 25820570 (2015) and 15673720 (2005)). The frequency of this variant in the general population, 0.00026 (8/30604 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 24, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: deficient in glycosylase activity and partially deficient in base excision repair activity (Bai et al., 2005; Komine et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.679C>T p.(Arg227Trp); This variant is associated with the following publications: (PMID: 15366000, 15673720, 19506731, 28127763, 30604180, 32923906, 17931073, 25820570, 21171015, 14991577, 27194394, 27799157, 20663686, 23605219, 23507534, 24470512, 28533537, 28152038, 32338768, 33258288, 30787465, 30613976, 23108399, 11801590, 34704405, 23561487) -

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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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Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial adenomatous polyposis 2 Pathogenic:7

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 241 of the MUTYH protein (p.Arg241Trp). This variant is present in population databases (rs34126013, gnomAD 0.03%). This missense change has been observed in individuals with colorectal cancer and/or polyposis (PMID: 14991577, 23561487, 24470512, 27194394). This variant is also known as c.679C>T (p.Arg227Trp). ClinVar contains an entry for this variant (Variation ID: 185274). 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: 15673720, 25820570). This variant disrupts the p.Arg241 amino acid residue in MUTYH. Other variant(s) that disrupt this residue have been observed in individuals with MUTYH-related conditions (PMID: 19732775; internal data), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Dec 13, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with tryptophan at codon 241 of the MUTYH protein. This variant is also known as c.679C>T (p.Arg227Trp) based on an alternative 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant disrupts MUTYH protein function (PMID: 15673720, 25820570). This variant has been reported as compound heterozygous with another pathogenic variant in multiple individuals affected with polyposis and/or colorectal cancer (PMID: 14991577, 15366000, 24470512, 27194394, 28533537, Color internal data), and as homozygous in two siblings affected with attenuated polyposis (parents were consanguineous) (PMID: 23561487). This variant has been identified in 18/281720 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Jan 04, 2017

Counsyl

Significance: Likely 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. -

Jul 02, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.721C>T (p.Arg241Trp) variant, also referred to as c.679C>T (p.Arg227Trp), has been reported in five studies in which it is found in a total of six MYH-associated polyposis patients, including two siblings in a homozygous state and four patients in a compound heterozygous state with one of the common pathogenic MUTYH missense variants (Isidro et al. 2004; Fleischmann et al. 2004; Bai et al. 2005; Torrezan et al. 2013; Guarinos et al. 2014). The variant was absent from 354 controls (Fleischmann et al. 2004) but is reported at a frequency of 0.00042 in the South Asian population of the Exome Aggregation Consortium. Functional studies demonstrated that the p.Arg241Trp variant has a severe defect in adenine (A) /7,8-dihydro-8-oxo-guanine binding and therefore in the ability to catalyze adenine excision from A/GO mismatches, one of the main functions of the protein. The p.Arg241Trp variant was also shown to have no detectable glycosylase activity and failed to complement mut Y-deficiency in E. coli. The variant does not affect binding to the hMSH2/hMSH6 complex (Bai et al. 2005; Komine et al. 2015). Based on the collective evidence, the p.Arg241Trp variant is classified as likely pathogenic for MYH-associated polyposis. -

Mar 13, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MUTYH p.Arg241Trp: This sequence change replaces arginine with tryptophan at codon 241 of the MUTYH protein (p.Arg241Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs34126013, ExAC 0.04%). This variant has been reported as heterozygous with another pathogenic variant in MUTYH in multiple individuals affected with polyposis and/or colorectal cancer (PMID: 24470512, 14991577, 27194394), and as homozygous in two siblings from a family affected with polyposis (PMID: 23561487). ClinVar contains an entry for this variant (Variation ID: 185274). In addition, in-silico prediction for this alteration shows pathogenic computational verdict based on 12 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL and SIFT vs 1 benign prediction from PrimateAI. Experimental studies suggest that this missense change disrupts MUTYH protein function in vitro and in a bacteria-based functional assay (PMID: 15673720, 25820570). Therefore, this variant has been classified as Likely Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Sep 08, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with tryptophan at codon 241 of the MUTYH protein. This variant is also known as c.637C>T (p.Arg213Trp) based on an alternative transcript (NM_001048174.2). 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 this variant was deficient in A/8-oxoG binding and glycosylase activities , and failed to complement mutY-deficiency in Escherichia coli (PMID: 15673720, 25820570). This variant has been reported as biallelic with another pathogenic variant in multiple individuals affected with polyposis and/or colorectal cancer (PMID: 15366000, 19394335, 23561487, 24470512, 27194394, 28533537, 34704405). This variant has been identified in 18/281720 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Jan 06, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R241W pathogenic mutation (also known as c.721C>T), located in coding exon 9 of the MUTYH gene, results from a C to T substitution at nucleotide position 721. The arginine at codon 241 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in conjunction with the common MUTYH founder mutations p.G396D (p.G382D) and p.Y179C (p.Y165C), other pathogenic/likely pathogenic MUTYH variants, and as homozygous in multiple patients with classic polyposis, attenuated polyposis, and/or colorectal cancer (Isidro G et al. Hum Mutat. 2004 Oct;24(4):353-4; Bai H et al. Nucleic Acids Res. 2005 Jan 26;33(2):597-604; Torrezan GT et al. Orphanet J Rare Dis. 2013 ;8:54; Guarinos C et al. Clin Cancer Res. 2014 Mar 1;20(5):1158-68; Win AK et al. Int J Cancer. 2016 Oct 1;139(7):1557-63; Khan N et al. Sci Rep. 2017 May 22;7(1):2214; Ambry internal data). Furthermore, the aforementioned co-occurrences are likely to be in trans due to multiple observances with different pathogenic or likely pathogenic MUTYH variants. In functional assays measuring glycosylase activity and DNA-binding activity, this variant demonstrated impaired protein function similar to the p.Y179C (p.Y165C) MUTYH founder mutation (Bai H et al. Nucleic Acids Res. 2005 Jan 26;33(2):597-604; Komine K et al. Hum Mutat. 2015 Jul;36(7):704-11). This alteration has also been identified in individuals diagnosed with male breast cancer, breast cancer and prostate cancer (Rizzolo P et al. Front Oncol, 2018 Dec;8:583; Lang GT et al. Ann Transl Med, 2020 Nov;8:1417; Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149). Of note, this alteration is also designated as p.R227W in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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

Jan 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.65	.;.;.;.;.;D;.;.;.;D;.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.0	.;.;.;.;.;H;.;.;.;.;.;.
PhyloP100		6.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.5	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.79
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		0.96
MVP		1.0
MPC		0.56
ClinPred		1.0	D
GERP RS		5.6
PromoterAI		0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.95
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs34126013; hg19: chr1-45798130; COSMIC: COSV106101378; COSMIC: COSV106101378;