rs765123255

Variant names:

• chr1-45333436-G-A
• rs765123255
• NM_001048174.2:c.241C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-45333436-G-A
• chr1-45333436-G-C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_001048174.2(MUTYH):​c.241C>T​(p.Arg81Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,614,090 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. R81G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 3.27
• Publications: 24 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 16 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 14 benign, 51 uncertain in NM_001048174.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-45333436-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 849076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 1-45333436-G-A is Pathogenic according to our data. Variant chr1-45333436-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 183896.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.241C>T	p.Arg81Trp	missense_variant	Exon 3 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.241C>T	p.Arg81Trp	missense_variant	Exon 3 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.829C>T		non_coding_transcript_exon_variant	Exon 7 of 21			ENSP00000499896.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251476 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461888 Hom.: 0 Cov.: 35 AF XY: 0.0000344 AC XY: 25 AN XY: 727244

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

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

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

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1112012

Other (OTH) AF: 0.0000662 AC: 4 AN: 60394

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

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: 0.000103 AC: 7 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000873 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:8

Oct 16, 2015

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 02, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2016

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.325C>T (p.Arg109Trp) missense variant in the MUTYH gene has been previously reported in multiple individuals affected with Familial Adenomatous Polyposis (Vogt et al., 2009; Shinmura et al., 2014; Nielsen M et al., 2009). In two unrelated individuals, this variant was observed in trans with a known pathogenic variant, Gly396Asp (Vogt et al., 2009; Yurgelun MB et al., 2015). Furthermore, an in vitro functional assay demonstrated that this variant resulted in reduced DNA glycosylase activity and impaired mutation-suppression activity (Shinmura et al., 2014). This variant is reported at low frequency in the population databases (Exome Sequencing Project = NA; 1000 Genomes = NA; and ExAC = 0.006%). Multiple in silico algorithms predict this variant to have a deleterious effect (CADD = 15.47; PolyPhen = 1.0; SIFT = 0.0). Ambry Genetics has classified this variant as Likely pathogenic. Therefore, this collective evidence supports the classification of the c.325C>T (p.Arg109Trp) as a recessive Likely pathogenic variant for Familial Adenomatous Polyposis. -

Sep 18, 2015

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. -

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 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 109 of the MUTYH protein (p.Arg109Trp). This variant is present in population databases (rs765123255, gnomAD 0.006%). This missense change has been observed in individual(s) with early-onset colorectal cancer, MUTYH-associated polyposis, and/or suspected Lynch syndrome (PMID: 19732775, 21520333, 24799981, 25980754). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 183896). 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: 24799981). For these reasons, this variant has been classified as Pathogenic. -

Apr 01, 2019

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:3

Mar 15, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in the apparently heterozygous state in individuals with Lynch syndrome-associated cancers and/or colon polyps, as well as other cancers (PMID: 17949294, 25980754, 35264596, 34308104); Published functional studies demonstrate a damaging effect: decreased DNA glycosylase activity, decreased ability to suppress 8-hydroxyguanine-induced mutations compared to wild type (PMID: 24799981); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.283C>T, Arg95Trp, and R81W; This variant is associated with the following publications: (PMID: 20725929, 28152038, 19732775, 19032956, 24799981, 17949294, 25980754, 26600934, 26694661, 21520333, 27253753, 19394335, 30604180, 33830941, 34308104, 35264596, 30291343, 32980694) -

Nov 03, 2021

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 18, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MUTYH c.325C>T (p.Arg109Trp) variant has been reported in the published literature as compound heterozygous with a pathogenic MUTYH variant in individuals with MUTYH-associated polyposis (PMIDs: 27705013 (2016), 27145315 (2016), 25980754 (2015), 19732775 (2009), 19527492 (2009), 19394335 (2009)). It was also mentioned in an individual with suspected Lynch syndrome (25980754 (2015)), urothelial cancer (PMID: 31844177 (2020)) and as heterozygous in an individual with early onset colorectal cancer (PMID: 24799981 (2014)). This variant was also reported in breast cancer cases as well as in reportedly healthy individuals in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MUTYH)). A functional study demonstrated that this variant has impaired DNA repair activity in vitro (PMID: 24799981 (2014)). The frequency of this variant in the general population, 0.000054 (7/129178 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. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Mar 17, 2025

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 109 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. A functional study has shown that this variant disrupts the DNA glycosylase activity of the MUTYH protein and its ability to suppress mutations (PMID: 24799981). This variant has been reported in the compound heterozygous state in three individuals affected with MUTYH-associated polyposis and colorectal cancer (PMID: 19394335, 19527492, 19732775; ClinVar SCV000517270.5) and in an individual suspected of having Lynch syndrome (PMID: 25980754). This variant has also been observed in a heterozygous individual affected with early-onset colorectal cancer (PMID: 24799981). This variant has been identified in 11/282856 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Aug 25, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R109W variant (also known as c.325C>T), located in coding exon 3 of the MUTYH gene, results from a C to T substitution at nucleotide position 325. The arginine at codon 109 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been identified, in conjunction with a pathogenic MUTYH mutation, in multiple patients with colorectal cancer and/or polyposis (Vogt et al. Gastroenterology. 2009;137:1976–1985; Yurgelun MB et al. Gastroenterology 2015 Sep;149:604-13.e20; Church J et al. Dis. Colon Rectum, 2016 Jun;59:565; Ambry internal data). This alteration was also identified in 1 of 34 patients with colorectal cancer under age 43 from a cohort of 685 Japanese patients and was associated with severely reduced MUTYH protein function (Shinmura K et al. Oxid Med Cell Longev 2014;2014:617351). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Carcinoma of colon Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Arg109Trp variant was identified in 2 of 438 proband chromosomes (frequency: 0.005) from Euorpean and Japanese individuals or families with MAP or early onset colorectal cancer (Nielsen 2009, Shinmura 2014); The variant was not identified in dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), MutDB, “Zhejiang Colon Cancer Database”, the ClinVar database, GeneInsight VariantWire database, UMD and COSMIC; nor was it previously identified in our laboratory. The variant was identified in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 6 of 121394 chromosomes (all heterozygotes; frequency: 4.94E-05) from a population of European (Non-Finnish) (4/66728 individuals) and South Asian (2/16512) individuals, but not in East Asian, African, Latino or European (Finnish) individuals; the variant was also identified in the InSiGHT Colon Cancer Gene Variant Database (3x) and HGMD. The p.Arg109 residue is conserved across mammals and lower organisms, and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Trp (Tryptophan) variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The p.Arg109Trp variant was identified in a Japanese early onset CRC patient (heterozygous germline, and not biallelic for MUTYH), and studies using DNA cleavage and supF forward mutation assays showed functional impairment through defective DNA glycosylase activity and impaired suppressive activity against mutations (Shinmura 2014). In a Dutch study evaluating histological and molecular aspects of MAP tumours, it was found that these tumours show similarities to sporadic and Lynch tumors. The variant co-occurred with the pathogenic p.Gly396Asp (Nielsen 2009). An additional European study looking at incidence of both malignant and benign extracolonic lesions in MAP patients, the variant co-occurred with the pathogenic p.Gly396Asp. (Vogt 2009) increasing the likelihood this variant is clinically significant. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as pathogenic. -

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	.;.;.;.;.;D;.;.;.;T;T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	.;.;.;.;.;H;.;.;.;.;.;.
PhyloP100		3.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-7.3	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;D;D;.;D;.;.;.
Vest4		0.93
MVP		0.98
MPC		0.56
ClinPred		1.0	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.87
gMVP		0.88
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs765123255; hg19: chr1-45799108; COSMIC: COSV109426199;