1-45332794-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_001128425.2(MUTYH):c.545G>A(p.Arg182His) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,614,056 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R182G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

MUTYH
NM_001128425.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16

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: 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 2 benign, 47 uncertain in NM_001128425.2

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, 0.989

PP5

Variant 1-45332794-C-T is Pathogenic according to our data. Variant chr1-45332794-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 182689.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_001128425.2 link	c.545G>A	p.Arg182His	missense_variant	Exon 7 of 16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2 link	c.461G>A	p.Arg154His	missense_variant	Exon 7 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MUTYH	ENST00000710952.2 link	c.545G>A	p.Arg182His	missense_variant	Exon 7 of 16		NM_001128425.2	ENSP00000518552.2
MUTYH	ENST00000456914.7 link	c.461G>A	p.Arg154His	missense_variant	Exon 7 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1 link	n.1049G>A		non_coding_transcript_exon_variant	Exon 11 of 21			ENSP00000499896.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251468

AF XY:

0.0000147

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0000299

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:

0.0000288

AC:

AN:

1112004

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

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:

0.0000131

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.00

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: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000340

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Pathogenic:8

Jan 17, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genomics England Pilot Project, Genomics England

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 29, 2019

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The variant, MUTYH c.545G>A (p.Arg182His) results in a non-conservative amino acid change located in the HhH-GPD domain 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 8.1e-06 in 246268 control chromosomes (gnomAD). The variant, c.545G>A has been reported in the literature in multiple individuals affected with Attenuated familial adenomatous polyposis and colorectal cancer (Morak_2010, Komine_2015, AlDubayan_2018, Yugelun_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Shinmura_2012). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 06, 2024

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 histidine at codon 182 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). Functional studies have shown that this variant severely impairs DNA glycosylase activity and ability to suppress mutations (PMID: 20848659, 23322991) and failed to complement a MutY-deficient bacteria strain (PMID: 25820570). This variant has been reported in compound heterozygous state with a pathogenic variant in multiple individuals affected with polyposis and colorectal cancer (PMID: 15366000, 16557584, 19394335, 20618354, 28135145, 29478780, 34704405). This variant has been identified in 3/251468 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occuring at the same position, p.Arg182Cys, is known to be pathogenic (Clinvar variation ID: 187280), indicating that arginine at this position is important for MUTYH protein function. Based on the available evidence, this variant is classified as Pathogenic. -

May 04, 2022

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 19, 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 histidine, which is basic and polar, at codon 182 of the MUTYH protein (p.Arg182His). This variant is present in population databases (rs143353451, gnomAD 0.002%). This missense change has been observed in individuals with MUTYH-associated polyposis (PMID: 15366000, 16557584, 19032956, 19394335, 20618354). This variant is also known as R154H and R168H. ClinVar contains an entry for this variant (Variation ID: 182689). 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: 20848659, 23322991). For these reasons, this variant has been classified as Pathogenic. -

Jul 02, 2018

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 11, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg182His variant in MUTYH has been reported in 6 compound heterozygous individuals with MUTYH-associated attenuated familial adenomatous polyposis (FAP; Isidro 2004, Aretz 2006, Jones 2009, Morak 2010, Marabelli 2016), 2 compound heterozygous individuals with colorectal cancer (CRC; DiGregorio 2006, Morak 2010), 1 heterozygous individual with CRC (Morak 2010), and 2 heterozygous individuals with FAP and/or CRC with no second allele specified (Nielsen 2009, Susswein 2016). This variant has also been reported in ClinVar (Variation ID 182689). This variant has been identified in 0.003% (3/113758) European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Arg182His variant may impact protein function (Goto 2010, Shinmura 2012). Computational prediction tools and conservation analysis suggest that the p.Arg182His variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for MUTYH-associated FAP in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2, PP3, PS3_Supporting. -

not provided

Pathogenic:2

Dec 21, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect: severely affected glycosylation and suppression of oxidative mutagenesis (Goto et al., 2010; Shinmura et al., 2012; Komine et al., 2015); 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; This variant is associated with the following publications: (PMID: 20848659, 25820570, 17273161, 19032956, 23507534, 30604180, 23322991, 15366000, 14961129, 16890597, 16557584, 19394335, 20618354, 23605219, 21901162, 28452373, 27783336, 29478780, 31589614, 16207212, 35418818, 30291343, 26681312, 32283892, 34704405, 35264596, 28135145, 34758253) -

Jun 30, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one patient with expected phenotype for this gene. Other pathogenic or likely pathogenic variants affect the same amino acid . In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Apr 30, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R182H pathogenic mutation (also known as c.545G>A), located in coding exon 7 of the MUTYH gene, results from a G to A substitution at nucleotide position 545. The arginine at codon 182 is replaced by histidine, an amino acid with highly similar properties. This pathogenic mutation has been identified in trans in several individuals with MAP phenotypes (Isidro et al. Hum Mutat 2004 Oct; 24(4):353-4; Di Gregorio et al. Gastroenterology 2006 Aug; 131(2):439-44; Aretz et al. Int J Cancer 2006 Aug 15;119(4): 807-14; Jones N et al. Gastroenterology. 2009 Aug;137(2):489-94, 494.e1; Morak M et al. Clin Genet. 2010 Oct;78(4):353-63). In vitro studies comparing wild-type protein and variant-type proteins demonstrated severely impaired DNA glycosylase activity associated with the p.R182H alelle (Goto et al. Hum Mutat 2010 Nov; 31(11):E1861-74). This alteration has also been reported as functionally defective by one group based on results of a site-directed mutagenesis E. coli study (Komine K et al. Hum. Mutat., 2015 Jul;36:704-11). Of note, this mutation is also designated as p.R168H in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Feb 20, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with histidine at codon 182 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Functional studies have shown that this variant severely impairs DNA glycosylase activity and ability to suppress mutations (PMID: 20848659, 23322991) and failed to complement a MutY-deficient bacteria strain (PMID: 25820570). This variant has been reported in the compound heterozygous state with a pathogenic variant in multiple individuals affected with polyposis and colorectal cancer (PMID: 15366000, 16557584, 19394335, 20618354, 28135145, 29478780, 34704405). This variant has been identified in 3/251468 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occuring at the same position, p.Arg182Cys, is known to be pathogenic (ClinVar Variation ID: 187280), indicating that arginine at this position is important for MUTYH protein function. Based on the available evidence, this variant is classified as Pathogenic. -

not specified

Pathogenic:1

Nov 02, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Gastric cancer;C3272841:Familial adenomatous polyposis 2

Pathogenic:1

Feb 24, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

MUTYH-related disorder

Pathogenic:1

Jan 22, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MUTYH c.545G>A variant is predicted to result in the amino acid substitution p.Arg182His. This variant is also known as p.Arg154His, p.Arg168His, and p.Arg179His in the literature. This variant was reported in the homozygous and compound heterozygous states in individuals with autosomal recessive MUTYH-associated polyposis (Isidro et al. 2004. PubMed ID: 15366000; Dell et al. 2021. PubMed ID: 34704405; Ercoskun et al. 2022. PubMed ID: 35418818). This variant was also reported in individuals with neuroblastoma, breast, pancreas, and thyroid cancers (Table S4, Bhai et al. 2021. PubMed ID: 34326862; Table S2, Guindalini et al. 2022. PubMed ID: 35264596; Table S8, Bonfiglio et al. 2023. PubMed ID: 36493725). Functional studies showed that this variant results in reduced DNA glycosylase activity and impaired suppression of oxidative mutagenesis (Goto et al. 2010. PubMed ID: 20848659; Shinmura et al. 2012. PubMed ID: 23322991; Komine et al. 2015. PubMed ID: 25820570). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182689/). A different nucleotide substitution affecting the same amino acid (p.Arg182Cys) has been reported to be causative for autosomal recessive MUTYH-associated polyposis (De Rosa et al. 2009. PubMed ID: 19279422; Komine et al. 2015. PubMed ID: 25820570). Taken together, the c.545G>A (p.Arg182His) variant is interpreted as pathogenic. -

Familial colorectal cancer type X

Pathogenic:1

Dec 01, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.64

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

0.52

MetaRNN

Pathogenic

0.99

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

-4.6

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

REVEL

Pathogenic

0.91

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

0.95

MutPred

0.97

.;.;.;.;.;.;.;.;Loss of methylation at R182 (P = 0.0286);.;.;.;

MVP

0.99

MPC

0.61

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.82

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over