rs750592289

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1PM2PM5PP5BP4

The NM_001048174.2(MUTYH):c.469C>T(p.Arg157Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 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. R157Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:6

Conservation

PhyloP100: 0.985

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 Likely_pathogenic. Variant got 6 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-45332785-C-T is described in Lovd as [Likely_pathogenic].

PP5

Variant 1-45332786-G-A is Pathogenic according to our data. Variant chr1-45332786-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 419386.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Likely_pathogenic=2}. Variant chr1-45332786-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-45332786-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.29497647). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2 linkuse as main transcript	c.469C>T	p.Arg157Trp	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.469C>T	p.Arg157Trp	missense_variant	7/16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 linkuse as main transcript	n.1057C>T		non_coding_transcript_exon_variant	11/21			ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251446

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135916

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:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

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:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 26, 2023	This missense variant replaces arginine with tryptophan at codon 185 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant has no detectable glycosylase activity and reduced substrate binding (PMID: 19953527, 20418187). This variant has been reported in individuals affected with colorectal cancer and polyposis (PMID: 18091433) or breast cancer (PMID: 32658311). This variant has been identified in 2/251446 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 10, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 185 of the MUTYH protein (p.Arg185Trp). 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. Experimental studies have shown that this missense change affects MUTYH function (PMID: 19953527, 20418187, 22252118). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 419386). This missense change has been observed in individual(s) with polyposis, colorectal cancer, and/or breast cancer (PMID: 18091433, 32658311). This variant is present in population databases (rs750592289, gnomAD 0.004%). -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2019	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as c.511C>T, p.Arg171Trp; This variant is associated with the following publications: (PMID: 19953527, 25820570, 18091433, 20418187, 25638157, 32658311) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2018	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 22, 2023	This missense variant replaces arginine with tryptophan at codon 185 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant has no detectable glycosylase activity and reduced substrate binding (PMID: 19953527, 20418187). This variant has been reported in individuals affected with colorectal cancer and polyposis (PMID: 18091433) or breast cancer (PMID: 32658311). This variant has been identified in 2/251446 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 07, 2024	The p.R185W variant (also known as c.553C>T), located in coding exon 7 of the MUTYH gene, results from a C to T substitution at nucleotide position 553. The arginine at codon 185 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was first reported in a male patient with colon cancer at age 49 and 90-100 polyps (Cattaneo F et al Genet. Med. 2007 Dec; 9(12):836-41). One functional analysis of this alteration using human proteins from a bacterial system suggests this alteration results in severe reduction in binding affinity as well as reduced adenine removal activity compared to the wild-type protein (D'Agostino VG et al DNA Repair (Amst.). 2010 Jun; 9(6):700-7). An additional study in which this alteration was expressed in Mutyh-/- mouse defective cells showed dysfunctional Base Excision Repair and goes on to suggest that the mutant protein produced by this alteration revealed a more pronounced phenotype than the simple loss of the Mutyh protein, suggesting a sort of dominant-negative effect (Molatore S et al Hum. Mutat. 2010 Feb; 31(2):159-66). Of note, this alteration is also designated as p.R171W (c.511C>T) in some published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Breast carcinoma

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Sep 10, 2021

- -

Familial cancer of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Center of Medical Genetics and Primary Health Care

Jul 15, 2020

ACMG Guidelines 2015 criteria The MUTYH gene variant p.Arg185Trp is in exon 7 and in the HhH-GPD domain (V118-249W aa) with a function in base-excision repair (PMID: 10706276). Experimental studies showed this missense change abolishes the glycosylase activity of the MUTYH protein (PMID: 20418187, 19953527) (PS3 Pathogenic Strong). It is in a mutation hotspot of 7 pathogenic, including missense pathogenic variants (PM1 Pathogenic Moderate). The allele frequency in GnomAD exomes is 0.00000795 which is less the threshold 0.0001 for recessive gene MUTYH, and the variant is not found in GnomAD genomes (PM2 Pathogenic Moderate). Meantime, majority of missense variants detected in MUTYH are pathogenic and known cause of disease (PP2 Pathogenic Supporting). In our study this variant was found in a 54-year-old female patient with unilateral breast cancer and a family history of cancer. Based on the evidence above we classified this variant as a Variant of Unknown Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Pathogenic

0.29

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.58

.;T

M_CAP

Uncertain

0.090

MetaRNN

Benign

0.29

T;T

MetaSVM

Uncertain

-0.14

PROVEAN

Benign

0.040

N;N

REVEL

Benign

0.10

Sift

Benign

0.11

T;T

Sift4G

Benign

0.21

T;T

Vest4

0.36

MutPred

0.33

Gain of sheet (P = 0.0166);Gain of sheet (P = 0.0166);

MVP

0.43

ClinPred

0.96

GERP RS

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

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