rs143353451

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM5PP3_ModeratePP5

The NM_001048174.2(MUTYH):c.461G>T(p.Arg154Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,614,058 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R154G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:3

Conservation

PhyloP100: 7.16

Publications

33 publications found

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 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

MUTYH links:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 47 uncertain in NM_001048174.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-45332795-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 940199.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.937

PP5

Variant 1-45332794-C-A is Pathogenic according to our data. Variant chr1-45332794-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 185441.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2 link	c.461G>T	p.Arg154Leu	missense_variant	Exon 7 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.461G>T	p.Arg154Leu	missense_variant	Exon 7 of 16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 link	n.1049G>T		non_coding_transcript_exon_variant	Exon 11 of 21			ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251468

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000279

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Pathogenic:2Uncertain:2

Nov 23, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 08, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with leucine at codon 182 of the MUTYH protein. This variant is also known as c.503G>T (p.Arg168Leu) based on an alternative transcript, NM_001048171. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. However, two other missense variants at this codon have been reported as loss-of-function in mutation suppressive activity and in vitro glycosylase activity assays (PMID: 20848659, 23322991). This variant has not been reported in individuals affected with hereditary cancer in the literature. Two different missense variants at the same codon, p.Arg182Cys and p.Arg182His, are reported as disease-causing in ClinVar (variation ID: 182689, 187280). These two other missense variants have been reported in heterozygosity with a second pathogenic MUTYH variant in individuals affected with MUTYH-associated polyposis and/or colorectal cancer (PMID: 15366000, 16207212, 16557584, 16890597, 19394335, 20618354). This variant has been identified in 3/282842 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Dec 19, 2024

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MUTYH c.545G>T (p.Arg182Leu) 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. Different variants affecting the same codon have been classified as pathogenic by our lab (c.544C>T, p.Arg182Cys and c.545G>A, p.Arg182His), supporting the critical relevance of codon 182 to MUTYH protein function. The variant allele was found at a frequency of 4e-06 in 251468 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.545G>T has been reported in the literature as a biallelic genotype with another pathogenic variant in trans in at-least one individual affected with MUTYH-Associated Polyposis (Thomas_2021) and has also been observed as an informative biallelic genotype in an individual with features of MUTYH-Associated Polyposis tested at our laboratory (internal data). The following publication has been ascertained in the context of this evaluation (PMID: 33130102). ClinVar contains an entry for this variant (Variation ID: 185441). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Nov 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 182 of the MUTYH protein (p.Arg182Leu). This variant is present in population databases (rs143353451, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of MUTYH-associated polyposis (internal data). 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: 185441). 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. This variant disrupts the p.Arg182 amino acid residue in MUTYH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15236166, 16890597, 18091433, 18301448, 19279422, 20848659, 23322991, 25820570). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Mar 05, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R182L variant (also known as c.545G>T), located in coding exon 7 of the MUTYH gene, results from a G to T substitution at nucleotide position 545. The arginine at codon 182 is replaced by leucine, an amino acid with dissimilar properties. This variant has been identified in in conjunction with other MUTYH variants in multiple individuals with features consistent with MUTYH-associated polyposis (Ambry internal data). 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 variant is interpreted as a disease-causing mutation. -

Jun 11, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with leucine at codon 182 of the MUTYH protein. This variant is also known as c.503G>T (p.Arg168Leu) based on an alternative transcript, NM_001048171. Computational prediction suggests that this variant may have deleterious impact on protein structure and function To our knowledge, functional studies have not been reported for this variant. This variant has been reported with a second pathogenic variant in individuals affected with MUTYH-associated disease (ClinVar Accession: SCV000215551.7, SCV000938889.6). This variant has been identified in 3/282842 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Two different missense variants at the same codon, p.Arg182Cys and p.Arg182His, are reported as disease-causing (ClinVar Variation ID: 182689, 187280). These two other missense variants have been reported in heterozygosity with a second pathogenic MUTYH variant in individuals affected with MUTYH-associated polyposis and/or colorectal cancer (PMID: 15366000, 16207212, 16557584, 16890597, 19394335, 20618354) and reported as loss-of-function in mutation suppressive activity and in vitro glycosylase activity assays (PMID: 20848659, 23322991). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided

Pathogenic:1

Jul 30, 2025

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; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

.;.;.;.;.;D;.;.;.;D;.;T

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.94

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.9

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

PhyloP100

7.2

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-6.5

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

REVEL

Pathogenic

0.93

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

0.98

MVP

1.0

MPC

0.62

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.88

Mutation Taster

=7/93

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over