rs765123255

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000456914.7(MUTYH):c.241C>T(p.Arg81Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,614,090 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R81G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

MUTYH
ENST00000456914.7 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 3.27

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in ENST00000456914.7

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-45333435-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 464711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

PP5

Variant 1-45333436-G-A is Pathogenic according to our data. Variant chr1-45333436-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45333436-G-A is described in Lovd as [Pathogenic]. Variant chr1-45333436-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2 linkuse as main transcript	c.325C>T	p.Arg109Trp	missense_variant	3/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2 linkuse as main transcript	c.241C>T	p.Arg81Trp	missense_variant	3/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2 linkuse as main transcript	c.325C>T	p.Arg109Trp	missense_variant	3/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7 linkuse as main transcript	c.241C>T	p.Arg81Trp	missense_variant	3/16	1	NM_001048174.2	ENSP00000407590	A1	Q9UIF7-6

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152202

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251476

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000527

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000950

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 109 of the MUTYH protein (p.Arg109Trp). This variant is present in population databases (rs765123255, gnomAD 0.006%). This missense change has been observed in individual(s) with early-onset colorectal cancer, MUTYH-associated polyposis, and/or suspected Lynch syndrome (PMID: 19732775, 21520333, 24799981, 25980754). 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: 183896). 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: 24799981). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 16, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 30, 2016	The c.325C>T (p.Arg109Trp) missense variant in the MUTYH gene has been previously reported in multiple individuals affected with Familial Adenomatous Polyposis (Vogt et al., 2009; Shinmura et al., 2014; Nielsen M et al., 2009). In two unrelated individuals, this variant was observed in trans with a known pathogenic variant, Gly396Asp (Vogt et al., 2009; Yurgelun MB et al., 2015). Furthermore, an in vitro functional assay demonstrated that this variant resulted in reduced DNA glycosylase activity and impaired mutation-suppression activity (Shinmura et al., 2014). This variant is reported at low frequency in the population databases (Exome Sequencing Project = NA; 1000 Genomes = NA; and ExAC = 0.006%). Multiple in silico algorithms predict this variant to have a deleterious effect (CADD = 15.47; PolyPhen = 1.0; SIFT = 0.0). Ambry Genetics has classified this variant as Likely pathogenic. Therefore, this collective evidence supports the classification of the c.325C>T (p.Arg109Trp) as a recessive Likely pathogenic variant for Familial Adenomatous Polyposis. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 18, 2015	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2024	Observed in the apparently heterozygous state in individuals with Lynch syndrome-associated cancers and/or colon polyps, as well as other cancers (PMID: 17949294, 25980754, 35264596, 34308104); Published functional studies demonstrate a damaging effect: decreased DNA glycosylase activity, decreased ability to suppress 8-hydroxyguanine-induced mutations compared to wild type (PMID: 24799981); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.283C>T, Arg95Trp, and R81W; This variant is associated with the following publications: (PMID: 20725929, 28152038, 19732775, 19032956, 24799981, 17949294, 25980754, 26600934, 26694661, 21520333, 27253753, 19394335, 30604180, 33830941, 34308104, 35264596, 30291343, 32980694) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 24, 2018	The best available variant frequency is uninformative because it is below the disease allele frequency. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 25, 2022	The p.R109W variant (also known as c.325C>T), located in coding exon 3 of the MUTYH gene, results from a C to T substitution at nucleotide position 325. The arginine at codon 109 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been identified, in conjunction with a pathogenic MUTYH mutation, in multiple patients with colorectal cancer and/or polyposis (Vogt et al. Gastroenterology. 2009;137:1976–1985; Yurgelun MB et al. Gastroenterology 2015 Sep;149:604-13.e20; Church J et al. Dis. Colon Rectum, 2016 Jun;59:565; Ambry internal data). This alteration was also identified in 1 of 34 patients with colorectal cancer under age 43 from a cohort of 685 Japanese patients and was associated with severely reduced MUTYH protein function (Shinmura K et al. Oxid Med Cell Longev 2014;2014:617351). 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 alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 10, 2023	This missense variant replaces arginine with tryptophan at codon 109 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant disrupts the DNA glycosylase activity of the MUTYH protein and its ability to suppress mutations (PMID: 24799981). This variant has been reported in the compound heterozygous state in individuals affected with MUTYH-associated polyposis and colorectal cancer (PMID: 19394335, 19527492, 19732775; ClinVar SCV000517270.5) and in an individual suspected of having Lynch syndrome (PMID: 25980754). This variant has also been observed in a heterozygous individual affected with early-onset colorectal cancer (PMID: 24799981). This variant has been identified in 11/282856 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Carcinoma of colon

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The p.Arg109Trp variant was identified in 2 of 438 proband chromosomes (frequency: 0.005) from Euorpean and Japanese individuals or families with MAP or early onset colorectal cancer (Nielsen 2009, Shinmura 2014); The variant was not identified in dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), MutDB, â€šÃ„ÃºZhejiang Colon Cancer Databaseâ€šÃ„Ã¹, the ClinVar database, GeneInsight VariantWire database, UMD and COSMIC; nor was it previously identified in our laboratory. The variant was identified in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 6 of 121394 chromosomes (all heterozygotes; frequency: 4.94E-05) from a population of European (Non-Finnish) (4/66728 individuals) and South Asian (2/16512) individuals, but not in East Asian, African, Latino or European (Finnish) individuals; the variant was also identified in the InSiGHT Colon Cancer Gene Variant Database (3x) and HGMD. The p.Arg109 residue is conserved across mammals and lower organisms, and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Trp (Tryptophan) variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The p.Arg109Trp variant was identified in a Japanese early onset CRC patient (heterozygous germline, and not biallelic for MUTYH), and studies using DNA cleavage and supF forward mutation assays showed functional impairment through defective DNA glycosylase activity and impaired suppressive activity against mutations (Shinmura 2014). In a Dutch study evaluating histological and molecular aspects of MAP tumours, it was found that these tumours show similarities to sporadic and Lynch tumors. The variant co-occurred with the pathogenic p.Gly396Asp (Nielsen 2009). An additional European study looking at incidence of both malignant and benign extracolonic lesions in MAP patients, the variant co-occurred with the pathogenic p.Gly396Asp. (Vogt 2009) increasing the likelihood this variant is clinically significant. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as pathogenic. -

Gastric cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.63

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

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.97

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.4

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-7.3

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

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.93

MVP

0.98

MPC

0.56

ClinPred

1.0

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.87

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over