rs745921592

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PVS1PM2PP3PP5_Very_Strong

The NM_001128425.2(MUTYH):c.586G>T(p.Glu196*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,030 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MUTYH
NM_001128425.2 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 2.51

Publications

5 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 19 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 1-45332678-C-A is Pathogenic according to our data. Variant chr1-45332678-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 406822.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.586G>T	p.Glu196*	stop_gained	Exon 8 of 16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2 link	c.502G>T	p.Glu168*	stop_gained	Exon 8 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MUTYH	ENST00000710952.2 link	c.586G>T	p.Glu196*	stop_gained	Exon 8 of 16		NM_001128425.2	ENSP00000518552.2
MUTYH	ENST00000456914.7 link	c.502G>T	p.Glu168*	stop_gained	Exon 8 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1 link	n.1090G>T		non_coding_transcript_exon_variant	Exon 12 of 21			ENSP00000499896.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152154

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251466

AF XY:

0.00000736

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:

0.00000205

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

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:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112004

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MUTYH p.Glu196X variant was identified in 1 of 1050 proband chromosomes (frequency: 0.0001) from individuals or families with FAP, in an anonymized North American study of patients at risk of FAP and HNPCC, who were negative for APC, MSH2 and MLH1 mutations (Eliason 2005). The variant was also identified by our laboratory in 1 individual with MAP. The variant was identified in the InSiGHT Colon Cancer Gene Variant Database-LOVD (by Eliason 2005) and not in dbSNP, Clinvitae database, COSMIC, ClinVar database, GeneInsight - COGR database, UMD databases, 1000 Genomes Project, Exome Variant Server project, or the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015). The p.Glu196X variant leads to a premature stop codon at position 196, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants in the MUTYH gene are an established mechanism of disease in MUTYH-associated polyposis. In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

Nov 21, 2017

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This pathogenic variant is denoted MUTYH c.586G>T at the cDNA level and p.Glu196Ter (E196X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, previously reported as MUTYH Glu182Ter (E182X) using alternate nomenclature, has been reported in the compound heterozygous state with a known pathogenic MUTYH variant in an individual with a history suspicious for familial adenomatous polyposis and negative APC testing (Eliason 2005). We consider this variant to be pathogenic. -

Apr 30, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MUTYH c.544G>T; p.Glu182Ter variant, also known as c.586G>T; p.Glu196Ter for transcript NM_001128425.1, is reported in the medical literature in at least one individual with suspected polyposis with an additional pathogenic variant. The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 406822) and only reported in 1 out of 246262 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Loss of function variants are a known pathogenic mechanism in MUTYH-associated polyposis (Nielsen 2011). Considering available information, this variant is classified as pathogenic. References: Eliason K et al. The potential for increased clinical sensitivity in genetic testing for polyposis colorectal cancer through the analysis of MYH mutations in North American patients. J Med Genet. 2005 Jan;42(1):95-6. Nielsen M et al. MUTYH-associated polyposis (MAP). Crit Rev Oncol Hematol. 2011 Jul;79(1):1-16. -

Familial adenomatous polyposis 2

Pathogenic:3

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Glu196*) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). This variant is present in population databases (rs745921592, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 15635083). This variant is also known as E182X. ClinVar contains an entry for this variant (Variation ID: 406822). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Aug 10, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Glu196X variant in MUTYH has been reported in one individual (compound heterozygous for a second pathogenic; G382D) during a screening (Eliason 2005 PMID: 15635083). It has also been identified in 0.001% (1/113756) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 406822). This nonsense variant leads to a premature termination codon at position 196, which is predicted to lead to a truncated or absent protein. Loss of function of the MUTYH gene is an established disease mechanism in autosomal recessive MAP. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive MAP. ACMG/AMP Criteria applied: PVS1, PM2. -

May 14, 2024

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, also known as E182X, changes 1 nucleotide in exon 8 of the MUTYH gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported with a co-variant in the same gene in an individual affected with familial adenomatous polyposis (PMID: 15635083). In a large international case-control meta-analysis, this variant was reported in 1/60466 breast cancer cases and 1/53461 controls (PMID: 33471991). This variant has been identified in 1/251466 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Jan 01, 2022

Sema4, Sema4

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Oct 28, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.E196* pathogenic mutation (also known as c.586G>T), located in coding exon 8 of the MUTYH gene, results from a G to T substitution at nucleotide position 586. This changes the amino acid from a glutamic acid to a stop codon within coding exon 8. This alteration has been reported in a likely compound heterozygous state in one of 219 individuals found negative for APC mutations during clinical genetic testing for familial adenomatous polyposis (Eliason K et al. J. Med. Genet. 2005 Jan;42:95-6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Apr 23, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.94

PhyloP100

2.5

Vest4

0.92

GERP RS

4.5

PromoterAI

0.0036

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.56

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.56

Position offset: 9

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