rs587781864

Positions:

chr1-45332791-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_001048174.2(MUTYH):c.464G>A(p.Gly155Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,614,076 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. G155S) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.46

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:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_001048174.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.936

PP5

Variant 1-45332791-C-T is Pathogenic according to our data. Variant chr1-45332791-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2 linkuse as main transcript	c.464G>A	p.Gly155Asp	missense_variant	7/16	ENST00000456914.7	NP_001041639.1	Q9UIF7-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7 linkuse as main transcript	c.464G>A	p.Gly155Asp	missense_variant	7/16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 linkuse as main transcript	n.1052G>A		non_coding_transcript_exon_variant	11/21			ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251458

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135918

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000134

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:

0.0000942

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 27, 2024	This missense variant replaces glycine with aspartic acid at codon 183 of the MUTYH protein. This variant is also known as c.506G>A (p.Gly169Asp) 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two siblings who have an in-trans pathogenic MUTYH variant and are affected with familial polyposis (PMID: 20223003) as well as an individual carrying a second pathogenic variant in MUTYH and affected with colorectal polyposis (DOI: 10.33878/2073-7556-2022-21-2-58-63 ). This variant has been detected in a breast cancer case-control meta-analysis in 2/60466 breast cancer cases and 1/53461 controls (PMID: 33471991). This variant has been identified in 1/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 16, 2023	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 183 of the MUTYH protein (p.Gly183Asp). This variant is present in population databases (rs587781864, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of MUTYH-associated polyposis in the homozygous or compound heterozygous states (PMID: 20223003; Invitae). 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: 141595). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 04, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 28, 2024	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2022	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; Also known as c.506G>A, p.Gly169Asp; This variant is associated with the following publications: (PMID: 20223003) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 11, 2024	The MUTYH c.548G>A (p.Gly183Asp) variant has been reported in the published literature in-trans with another pathogenic MUTYH variant in an individual with familial adenomatous polyposis (PMID: 20223003 (2006)). In addition, this variant has been reported in-trans with a second MUTYH variant in individuals with a personal and family history of MUTYH-associated polyposis (personal communication with Ambry Genetics related to ClinVar ID: 141595). The frequency of this variant in the general population, 0.000004 (1/251458 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 damaging. Based on the available information, this variant is classified as likely pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 19, 2022	The p.G183D pathogenic mutation (also known as c.548G>A), located in coding exon 7 of the MUTYH gene, results from a G to A substitution at nucleotide position 548. The glycine at codon 183 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported in conjunction with another pathogenic MUTYH mutation in two brothers with polyposis (Skrzypczak M et al. Hered. Cancer Clin. Pract. 2006;4:43-7). In addition, this alteration has been identified in several individuals with a second known MUTYH mutation in trans and a personal and family history consistent with MUTYH-associated polyposis (MAP) (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 05, 2023	This missense variant replaces glycine with aspartic acid at codon 183 of the MUTYH protein. This variant is also known as c.506G>A (p.Gly169Asp) 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two siblings who have an in-trans pathogenic MUTYH variant and are affected with familial polyposis (PMID: 20223003) as well as an individual carrying a second pathogenic variant in MUTYH and affected with colorectal polyposis (DOI: 10.33878/2073-7556-2022-21-2-58-63 ). This variant has been detected in a breast cancer case-control meta-analysis in 2/60466 breast cancer cases and 1/53461 controls (PMID: 33471991). This variant has been identified in 1/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Colon cancer

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

Apr 26, 2019

The MUTYH p.Gly183Asp variant was identified in 1 of 180 proband chromosomes (frequency: 0.006) from Polish individuals or families with FAP (Skrzypczak 2006). In this study the proband was affected with familial polyposis but negative for an APC pathogenic variant, and the variant co-occurred in trans with a pathogenic MUTYH variant (494A>G, Y165C). Similar observations have been made by our laboratory in two individuals both with MUTYH-related disease and with co-occurring MUTYH pathogenic variants (c.536A>G, p.Tyr179Cys and c.1187G>A, p.Gly396Asp) however phase was not determined. In discussion with additional clinical laboratories we identified multiple affected patients with this variant and a co-occurring pathogenic MUTYH variant, although phase was generally undetermined there was one case where phase was determined to be trans. The variant was also identified in dbSNP (ID: rs587781864) as “With Likely pathogenic” allele, and in ClinVar (classified with conflicting interpretations of pathogenicity; submitters: pathogenic by Ambry Genetics, likely pathogenic by GeneDx and Color, and uncertain significance by Invitae). The variant was identified in control databases in 1 of 246272 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017), observed in the following population: Finnish in 1 of 22300 chromosomes (freq: 0.00005) while not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian and South Asian populations. The p.Gly183 residue is conserved in mammals and 3 of 4 computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) predict that the variant will impact the function of the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

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

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

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

MetaRNN

Pathogenic

0.94

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

MetaSVM

Uncertain

0.0092

MutationAssessor

Uncertain

2.2

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

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-4.5

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

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.0040

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

Polyphen

1.0

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

Vest4

0.87

MutPred

0.82

.;.;.;.;.;.;.;.;Loss of methylation at R182 (P = 0.0471);.;.;.;

MVP

0.95

MPC

0.62

ClinPred

0.97

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

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

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