NM_001048174.2:c.736C>T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_001048174.2(MUTYH):c.736C>T(p.Arg246Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,461,788 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. R246Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 5.71

Variant links:

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 links:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_001048174.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-45332278-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41764.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=7, Uncertain_significance=8, Pathogenic=2, not_provided=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.879

PP5

Variant 1-45332279-G-A is Pathogenic according to our data. Variant chr1-45332279-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449417.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 link	c.736C>T	p.Arg246Trp	missense_variant	Exon 10 of 16	ENST00000456914.7	NP_001041639.1	Q9UIF7-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7 link	c.736C>T	p.Arg246Trp	missense_variant	Exon 10 of 16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 link	n.1324C>T		non_coding_transcript_exon_variant	Exon 14 of 21			ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000800

AC:

AN:

250086

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135472

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461788

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Pathogenic:5

Apr 24, 2019

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 30, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with tryptophan at codon 274 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant was categorized as functionally deficient (PMID: 25820570). This variant has been reported as biallelic with another MUTYH allele in individuals affected with MUTYH-associated polyposis (PMID: 16134147, 19732775, 26511139) and as a single in an individual affected with breast cancer (PMID: 26976419). This variant has been identified in 2/250086 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Sep 18, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg274Trp variant in MUTYH has been reported in the compound heterozygous state at least 2 individuals with MUTYH-associated polyposis (MAP) who had a sec ond pathogenic variant in MUTYH (Aceto 2005, Aretz 2005, Vogt 2009). Additionall y, it segregated with disease in at least one affected family member (Aceto 2005 ). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 449417) and has been identified in 1/33562 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Arg274Trp variant may impact protein function (Komine 2 015); however, these types of assays may not accurately represent biological fun ction. Computational prediction tools and conservation analysis support that the p.Arg274Trp variant may impact the protein. In summary, although additional stu dies are required to fully establish its clinical significance, this variant mee ts criteria to be classified as likely pathogenic for autosomal recessive MAP. A CMG/AMP criteria applied: PM2, PM3, PP1, PP3, PS3_Supporting. -

Jan 12, 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 274 of the MUTYH protein (p.Arg274Trp). This variant is present in population databases (rs769237459, gnomAD 0.003%). This missense change has been observed in individual(s) with MUTYH-associated polyposis (PMID: 16134147, 19032956, 19394335, 19732775; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 449417). 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: 25820570). For these reasons, this variant has been classified as Pathogenic. -

Feb 09, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Aug 15, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect: defective function in a MutY-deficient E. coli complementation assay (PMID: 25820570); This variant is associated with the following publications: (PMID: 19032956, 16134147, 28349240, 26976419, 23770606, 19394335, 16557584, 19725997, 26511139, 19732775, 34426522, Feng2021[Abstract], 11092888, 11160897, 33471974, 36988593, 25820570, 36655350, 34981295, 36243179) -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Nov 22, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 06, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R274W variant (also known as c.820C>T), located in coding exon 10 of the MUTYH gene, results from a C to T substitution at nucleotide position 820. The arginine at codon 274 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in the literature in a compound heterozygous state with another MUTYH mutation in multiple individuals with adenomatous polyposis and/or GI cancers (Aceto GM et al, J. Exp. Clin. Cancer Res. 2015 ; 34():131; Aceto G et al, Hum. Mutat. 2005 Oct; 26(4):394; Vogt S et al, Gastroenterology 2009 Dec; 137(6):1976-85.e1-10; Aretz S et al. Int. J. Cancer 2006 Aug;119(4):807-14). A functional analysis of this alteration using E. coli complementation, protein stability, and subcellular localization in mammalian cells indicated that this alteration was functionally defective (Komine K et al, Hum. Mutat. 2015 Jul; 36(7):704-11). Of note, this alteration is also designated as p.R260W (c.778C>T) in published literature. Another alteration at the same codon, p.R274Q (c.821G>A), has been detected in conjunction with different pathogenic MUTYH founder mutations in individuals with adenomatous polyposis; however, the phase (whether in cis or trans) is not confirmed (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Gastric cancer;C3272841:Familial adenomatous polyposis 2

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PM3+PP1+PP4+PP3 -

Gastric cancer

Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

MUTYH-related disorder

Pathogenic:1

Jun 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MUTYH c.820C>T variant is predicted to result in the amino acid substitution p.Arg274Trp. This variant was reported in multiple individuals with Adenomatous polyposis coli (Table 2. Aceto et al 2005. PubMed ID: 16134147; Vogt S et al 2009. PubMed ID: 19732775; Table 1. Komine K et al 2015. PubMed ID: 25820570; Table1. Nielsen M et al 2008. PubMed ID: 19032956; Jones N et al. 2009 PubMed ID: 19394335). It has been observed to segregate with disease in related individuals (Aceto et al. 2005. PubMed ID: 16134147). Experimental studies and in silico analysis support that this missense variant has a deleterious effect and is functionally defective (Komine K et al. 2015. PubMed ID: 25820570). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD and is listed in Clinvar as pathogenic/likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/449417/). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.43

.;.;.;.;.;T;.;.;.;T;.;T

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

.;D;.;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.88

D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

4.6

.;.;.;.;.;H;.;.;.;.;.;.

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-6.7

D;D;D;D;D;D;D;D;D;.;D;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

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, 1.0

.;.;.;.;.;D;D;.;D;.;.;.

Vest4

0.72

MutPred

0.68

.;.;.;.;.;.;.;.;Loss of disorder (P = 0.0143);.;.;.;

MVP

0.99

MPC

0.56

ClinPred

1.0

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.84

gMVP

0.78

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over