1-45330526-C-T

Position:

chr1-45330526-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBP6

The NM_001048174.2(MUTYH):c.1424G>A(p.Gly475Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,609,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. G475V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000057 ( 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: 2.13

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_benign. Variant got -1 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain in NM_001048174.2

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0199987).

BP6

Variant 1-45330526-C-T is Benign according to our data. Variant chr1-45330526-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134866.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=14, Likely_benign=2, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2 link	c.1424G>A	p.Gly475Glu	missense_variant	15/16	ENST00000456914.7	NP_001041639.1	Q9UIF7-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7 link	c.1424G>A	p.Gly475Glu	missense_variant	15/16	1	NM_001048174.2	ENSP00000407590.2		Q9UIF7-6
ENSG00000288208	ENST00000671898.1 link	n.2012G>A		non_coding_transcript_exon_variant	19/21			ENSP00000499896.1		A0A5F9ZGZ0

Frequencies

GnomAD3 genomes

AF:

0.000664

AC:

101

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00234

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000132

AC:

AN:

243210

Hom.:

AF XY:

0.0000685

AC XY:

AN XY:

131370

show subpopulations

Gnomad AFR exome

AF:

0.00183

Gnomad AMR exome

AF:

0.0000590

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:

0.00000912

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.0000569

AC:

AN:

1457520

Hom.:

Cov.:

AF XY:

0.0000511

AC XY:

AN XY:

724584

show subpopulations

Gnomad4 AFR exome

AF:

0.00216

Gnomad4 AMR exome

AF:

0.0000452

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.000663

AC:

101

AN:

152256

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00233

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000420

Hom.:

Bravo

AF:

0.000654

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000140

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:6

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 02, 2024	The MUYTH c.1508G>A (p.Gly503Glu) missense variant has a maximum subpopulation frequency of 0.23% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function. This variant was found to cause partial loss of MUTYH function in a bacterial complementation assay (PMID: 25820570). This variant has been reported in individuals with colorectal cancer and/or Lynch syndrome (PMID: 25980754, 28944238). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 503 of the MUTYH protein (p.Gly503Glu). This variant is present in population databases (rs3219494, gnomAD 0.2%). This missense change has been observed in individual(s) with endometrial cancer (PMID: 25980754, 26689913). This variant is also known as c.1466G>A. ClinVar contains an entry for this variant (Variation ID: 134866). 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 does not substantially affect MUTYH function (PMID: 25820570). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 22, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces glycine with glutamic acid at codon 503 of the MUTYH protein. This variant is also known as c.1466G>A (p.Gly489Glu) based on an alternative transcript (NM_001048171). Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported this variant as causing partial loss of MUTYH function in an bacterial complementation assay (PMID: 25820570). This variant has been reported in an individual affected with Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754). This variant has been identified in 60/274602 chromosomes (56/24032 African 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	Counsyl	Apr 13, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jan 26, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 26, 2021	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 22, 2023	This missense variant replaces glycine with glutamic acid at codon 503 of the MUTYH protein. This variant is also known as c.1466G>A (p.Gly489Glu) based on an alternative transcript (NM_001048171). Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported this variant as causing partial loss of MUTYH function in a bacterial complementation assay (PMID: 25820570). This variant has been reported in an individual affected with Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754). This variant has been identified in 60/274602 chromosomes (56/24032 African 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. -

not specified

Uncertain:2Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 25, 2018	The p.Gly503Glu variant in MUTYH has been reported in one individual with clinic al features of Lynch Syndrome as well as in one young reportedly healthy individ ual (Bodian 2014). This variant has also been reported by other clinical laborat ories in Clinvar (Variation ID: 134866) and has been identified in 0.22% (51/231 22) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org; dbSNP rs3219494). Although this variant has been seen i n the general population, its frequency is not high enough to rule out a pathoge nic role. In vitro functional studies provide some evidence that the p.Gly503Glu variant may impact protein function (Komine 2015). Additionally, computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p .Gly503Glu variant is uncertain. ACMG/AMP Criteria applied: PS3_Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 23, 2024	Variant summary: MUTYH c.1508G>A (p.Gly503Glu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 243210 control chromosomes, predominantly at a frequency of 0.0018 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (0.00013 vs 0.0046), allowing no conclusion about variant significance. c.1508G>A has been reported in the literature in colorectal/breast cancer cases and in the TGCA cohort (e.g. Yurgelun_2015, Lu_2015, Tung_2015, Purrington_2020, Barreiro_2022, Guindalini_2022, de Oliveria_2022). These reports do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. At least one publication has reported experimental evidence evaluating an impact on protein function and found the variant caused a partial defect in an E.coli model system (Komine 2015). The following publications have been ascertained in the context of this evaluation (PMID: 34816434, 24728327, 35264596, 25820570, 26689913, 32868316, 25186627, 25980754, 35534704). ClinVar contains an entry for this variant (Variation ID: 134866). Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 19, 2024	The MUTYH c.1508G>A (p.Gly503Glu) variant has been reported in the published literature in individuals with breast cancer (PMID: 25186627 (2015), 32868316 (2020), 35264596 (2022), 35534704 (2022)), suspected Lynch syndrome (PMID: 25980754 (2015)), and endometrial cancer (PMID: 26689913 (2015)). A published functional study has shown that this variant displays partially defective base excision repair activity without affecting protein expression or localization (PMID: 25820570 (2015)). The frequency of this variant in the general population, 0.0023 (56/24032 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2025	In silico analysis indicates that this missense variant does not alter protein structure/function; Published functional studies demonstrate partially defective base excision repair activity in a yeast-based complementation assay and reduced protein expression (PMID: 25820570); This variant is associated with the following publications: (PMID: 25186627, 25980754, 24728327, 21167187, 21153778, 26689913, 32868316, 30122538, 34816434, 35534704, 35264596, 25820570) -

Gastric cancer;C3272841:Familial adenomatous polyposis 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 27, 2024

- -

MUTYH-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 15, 2022

The MUTYH c.1508G>A variant is predicted to result in the amino acid substitution p.Gly503Glu. This variant has been reported in an individual with suspected Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754), in individuals with breast cancer (Supplementary Table, Tung et al. 2015. PubMed ID: 25186627; Table S3, Purrington et al. 2020. PubMed ID: 32868316), and in individuals from a healthy, ancestrally diverse genome sequencing cohort (Table S1, Bodian et al. 2014. PubMed ID: 24728327). Functional studies also suggest this variant impacts base excision repair activity of the MUTYH protein (Komine et al. 2015. PubMed ID: 25820570). This variant is reported in 0.23% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-45796198-C-T) and is interpreted as uncertain significant in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/134866/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

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

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.87

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

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.020

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

MetaSVM

Uncertain

-0.072

MutationAssessor

Uncertain

2.6

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

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.8

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

REVEL

Benign

0.27

Sift

Uncertain

0.0050

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

Sift4G

Uncertain

0.015

D;T;T;T;T;T;D;T;T;D;D;T

Polyphen

0.78, 0.96, 0.40

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

Vest4

0.48

MVP

0.89

MPC

0.37

ClinPred

0.090

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.14

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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