1-45330550-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_001048174.2(MUTYH):c.1400G>A(p.Arg467His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,608,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. R467C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14B:2O:1

Conservation

PhyloP100: 2.15

Publications

6 publications found

Variant links:

COSMIC-nc: COSV58345131

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: Uncertain_significance. The variant received 0 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 20 benign, 50 uncertain in NM_001048174.2

BP4

Computational evidence support a benign effect (MetaRNN=0.254276).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2 link	c.1400G>A	p.Arg467His	missense_variant	Exon 15 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.1400G>A	p.Arg467His	missense_variant	Exon 15 of 16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 link	n.1988G>A		non_coding_transcript_exon_variant	Exon 19 of 21			ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000207

AC:

AN:

241088

AF XY:

0.0000231

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000184

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000135

AC:

197

AN:

1456638

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

724096

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33360

American (AMR)

AF:

0.0000227

AC:

AN:

44128

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26012

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39572

South Asian (SAS)

AF:

0.0000353

AC:

AN:

85098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53144

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000168

AC:

186

AN:

1109386

Other (OTH)

AF:

0.0000831

AC:

AN:

60176

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:

0.0000723

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41426

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.0000857

Hom.:

Bravo

AF:

0.0000567

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Uncertain:5Other:1

Mar 17, 2022

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MUTYH c.1484G>A (p.Arg495His) missense change has a maximum subpopulation frequency of 0.0069% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/1-45796222-C-T?dataset=gnomad_r2_1). In silico tools are not in agreement about the effect of this variant on protein function. Functional studies have examined the DNA glycosylase activity and ability to suppress mutations caused by 8-hydroxyguanine, an oxidized form of guanine, for this variant by a DNA cleavage activity assay and supF forward mutation assay, respectively. Both assays demonstrated that this variant behaves similar to the wild-type (BS3_supporting; PMID: 26694661). This variant has been reported as heterozygous in an individual with endometrial cancer (PMID: 27443514) and a pediatric precursor B-ALL patient (PMID: 33332384). It has also been identified in an individual with breast cancer and several family members with various cancer types (PMID: 30374176); other germline variants, including a likely pathogenic variant in PMS2, were also identified in the family. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BS3_supporting. -

Jun 04, 2016

Counsyl

Significance:Uncertain significance

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. -

GenomeConnect - Invitae Patient Insights Network

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Uncertain significance and reported on 06-04-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

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 495 of the MUTYH protein (p.Arg495His). This variant is present in population databases (rs144111588, gnomAD 0.007%). This missense change has been observed in individual(s) with endometrial cancer (PMID: 27443514). ClinVar contains an entry for this variant (Variation ID: 142440). 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 tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Sep 23, 2024

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 histidine at codon 495 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with melanoma (PMID: 29684080), at least one individual affected with endometrial cancer (PMID: 26832770, 27443514), and reported to occur in 0.12% of the Japanese population (PMID: 26694661). This variant has been identified in 8/272492 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. -

Apr 01, 2019

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Uncertain:3Benign:1

Aug 21, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In the published literature, this variant has been reported in individuals with endometrial cancer (PMID: 27443514 (2016)), melanoma (PMID: 29684080 (2018)), and breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)). This variant was also reported in unaffected individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)). The frequency of this variant in the general population, 0.000032 (4/123842 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Dec 17, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in individuals with endometrial cancer or renal cell carcinoma, as well as co-observed with a BRCA1 pathogenic variant in an individual with breast and ovarian cancer (PMID: 27443514, 37095444, 34326862); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25188385, 26694661, 28577310, 37095444, 36243179, 27443514, 23108399, 34326862, 33471991, 29684080) -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MUTYH: BP4, BS3:Supporting -

May 03, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4, PM2 -

not specified

Uncertain:3

Jun 16, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MUTYH c.1484G>A (p.Arg495His) results in a non-conservative amino acid change in the encoded protein sequence. The variant allele was found at a frequency of 2.1e-05 in 241088 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1484G>A has been reported in Lynch Syndrome patients in the literature, one in the tumor of a patient who carried a likely pathogenic MSH2 germline variant, as well as in the germline of a patient carrying a pathogenic MSH6 variant (Vargas-Parra_2017, Ring_2016). However, due to the predominantly recessive mode of inheritance attributed to variants in MUTYH, the possibility of incidental carrier status for a pathogenic variant cannot be excluded. The DNA glycosylase activity and ability to suppress mutations caused by 8-hydroxyguanine, an oxidized form of guanine, were examined for the nine variants of type 2 MUTYH, a nuclear form of the enzyme, by DNA cleavage activity assay and supF forward mutation assay, respectively (Shinmura_2016). The variant was similar to WT in DNA glycosylase activity and mutation frequency of the supF gene. The following publications have been ascertained in the context of this evaluation (PMID: 27443514, 26694661, 28577310, 30374176, 36702877, 35991532, 34816434, 32321774, 36243179, 26673799, 37095444, 34326862). ClinVar contains an entry for this variant (Variation ID: 142440). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 27, 2019

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Apr 21, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Dec 15, 2022

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with histidine at codon 495 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with melanoma (PMID: 29684080) and at least one individual affected with endometrial cancer (PMID: 26832770, 27443514). This variant has been identified in 8/272492 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. -

Mar 01, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Carcinoma of colon

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The p.Arg495His variant was not identified in the literature. This residue is conserved in mammals but not lower organisms such as chicken or zebrafish where a Lysine (Lys) is present at this position. In addition, computational analyses (PolyPhen, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein, but this information is not very predictive of pathogenicity. This variant was identified in the dbSNP database (ID: rs144111588) but was not validated and in the exome variant server in a European cohort with a frequency of 0.00023 increasing the likelihood that this may be a low frequency rare variant in this population of origin. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

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

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.82

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

M_CAP

Benign

0.034

MetaRNN

Benign

0.25

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.5

.;.;.;.;.;.;M;.;.;.;.;.

PhyloP100

2.2

PrimateAI

Benign

0.37

PROVEAN

Benign

-2.1

N;N;N;N;N;N;N;N;N;N;N;.

REVEL

Uncertain

0.46

Sift

Uncertain

0.0050

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

Sift4G

Uncertain

0.019

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

Polyphen

0.36, 0.47, 0.017

.;.;.;.;.;.;B;P;.;.;B;.

Vest4

0.44

MVP

0.93

MPC

0.14

ClinPred

0.34

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.11

gMVP

0.26

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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