rs200495564

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong

The NM_001048174.2(MUTYH):c.649C>T(p.Arg217Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging 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. R217L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14U:1

Conservation

PhyloP100: 7.25

Publications

35 publications found

Variant links:

COSMIC-nc: COSV58344430

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 14 ACMG points.

PM1

In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 35 uncertain in NM_001048174.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-45332445-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2733895.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.92

PP5

Variant 1-45332446-G-A is Pathogenic according to our data. Variant chr1-45332446-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 41761.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.649C>T	p.Arg217Cys	missense_variant	Exon 9 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.649C>T	p.Arg217Cys	missense_variant	Exon 9 of 16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 link	n.1237C>T		non_coding_transcript_exon_variant	Exon 13 of 21			ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152206

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:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000559

AC:

AN:

250276

AF XY:

0.0000516

show subpopulations

Gnomad AFR exome

AF:

0.0000620

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000548

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461766

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.000134

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1111984

Other (OTH)

AF:

0.0000166

AC:

AN:

60390

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:

0.0000394

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41564

American (AMR)

AF:

0.00

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000414

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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:

0.0000271

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Pathogenic:6

Feb 05, 2021

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MUTYH c.733C>T (p.Arg245Cys) 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. The variant allele was found at a frequency of 5.6e-05 in 250436 control chromosomes (gnomAD and publication data). This frequency is not higher than expected for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (5.6e-05 vs 0.0046), allowing no conclusion about variant significance. c.733C>T has been reported in the literature in multiple individuals affected with adenomatous polyposis, either in homozygosity (Miyaki_2005, Olschwang_2007), or in compound heterozygosity with known- or likely pathogenic variants (Ruggieri_2013, Takao_2017, Furlan_2017). Functional studies indicated that the variant mildly diminishes RNA and protein expression, but completely abolishes DNA glycosylase activity (Ruggieri_2013), and partially impairs base excision repair (Komine_2015). Additionally, other variants at this amino acid position are reported in patients (p.Arg245His, p.Arg245Ser and p.Arg245Leu), suggesting this residue is critical for function. Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=6) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 08, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 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 cysteine, which is neutral and slightly polar, at codon 245 of the MUTYH protein (p.Arg245Cys). This variant is present in population databases (rs200495564, gnomAD 0.02%). This missense change has been observed in individuals with familial adenomatous polyposis and/or MUTYH-associated polyposis (PMID: 15890374, 17949294, 23108399). This variant is also known as c.691C>T (p.Arg231Cys). ClinVar contains an entry for this variant (Variation ID: 41761). 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: 23108399, 25820570). For these reasons, this variant has been classified as Pathogenic. -

Mar 24, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

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 cysteine at codon 245 of the MUTYH protein. This variant is also known as c.691C>T (p.Arg231Cys) 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). Functional studies have reported this variant to be non-functional in MUTYH glycosylase assay (PMID: 23108399) and complementation of MUTYH-deficient bacteria (PMID: 25820570). This variant has been observed as a homozygous variant and compound heterozygous variant with a pathogenic co-variant in individuals affected with colorectal cancer and/or multiple colorectal adenomas and polyps (PMID: 15890374, 17949294, 23108399, 34775073). This variant has also been identified in an individual affected with breast cancer (PMID: 34026625). This variant has been identified in 14/250276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

not provided

Pathogenic:3Uncertain:1

Jul 29, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been reported in multiple unrelated individuals with MUTYH-Associated Polyposis (MAP) and colorectal cancer in the published literature (PMIDs: 28141798 (2017), 23108399 (2013)),17949294 (2007), and 15890374 (2005)). Additionally, functional studies demonstrate a damaging effect of this variant on MUTYH protein function (PMIDs: 23108399 (2013) and 25820570 (2015)). Based on the available information, this variant is classified as pathogenic. -

Apr 02, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in the homozygous or compound heterozygous state in individuals with multiple polyps and colorectal cancer (Miyaki et al., 2005; Olschwang et al., 2007; Ruggieri et al., 2013; Gunaratnam et al., 2016; Furlan et al., 2017; Takao et al., 2018; Villy et al., 2021); Published functional studies demonstrate a damaging effect: absent DNA glycosylase activity, decreased MUTYH transcript and protein expression levels, and partially defective base excision repair (Ruggieri et al., 2013; Komine et al., 2015); 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: 23605219, 22744763, 24620956, 19725997, 17949294, 15890374, 22703879, 21443744, 22865608, 25655665, 23108399, 25820570, 26684191, 28087410, 28152038, 30564557, 30787465, 34775073, 32980694, 31739127, 19506731, 17703316, 23507534, 29915346, 11801590, 31203172, 24569162, 31104418, 32821650, 32665031, 27021195, 29330641, 34026625, 34308104, 30487145, 28141798) -

Jan 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Apr 05, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 16, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R245C pathogenic mutation (also known as c.733C>T), located in coding exon 9 of the MUTYH gene, results from a C to T substitution at nucleotide position 733. The arginine at codon 245 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been identified in the homozygous state and/or in conjunction with other MUTYH variant(s) in individual(s) with features consistent with MUTYH-associated polyposis (Miyaki M et al. Mutat. Res. 2005 Oct 15;578(1-2):430-3; Olschwang S et al. Genet Test. 2007 Fall;11(3):315-20; Ruggieri V et al. Oncogene, 2013 Sep;32:4500-8; Ambry internal data). Current evidence supports codon 245 as a functionally important mutation hotspot, with multiple other missense alterations having been described as pathogenic or deficient in critical protein function in the literature (Aceto G et al. Hum Mutat. 2005 Oct;26(4):394; Vogt S et al. Gastroenterology. 2009 Dec;137(6):1976-85.e1-10; Bai H et al. Cancer Lett. 2007 May 18;250(1):74-81). In addition, a functional assay showed that p.R245C, which exists in a highly conserved and catalytic domain, results in partially defective protein expression levels compared to wild-type (Komine K et al. Hum. Mutat., 2015 Jul;36:704-11). Of note, this alteration is also described as p.R231C in published literature. 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 available evidence, this alteration is classified as a pathogenic mutation. -

Familial colorectal cancer

Pathogenic:1

Jan 01, 2017

Snyder Lab, Genetics Department, Stanford University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Gastric cancer;C3272841:Familial adenomatous polyposis 2

Pathogenic:1

Apr 19, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Gastric cancer

Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.65

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

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.92

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

5.0

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

PhyloP100

7.3

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-7.5

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

REVEL

Pathogenic

0.94

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

0.99

MVP

0.98

MPC

0.64

ClinPred

1.0

GERP RS

4.7

PromoterAI

-0.0042

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.93

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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