NM_001128425.2:c.1508G>A

Variant names:

• chr1-45330526-C-T
• rs3219494
• NM_001128425.2:c.1508G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001128425.2(MUTYH):​c.1508G>A​(p.Gly503Glu) 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. G503V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000057 (0 hom.)
• Consequence: MUTYH NM_001128425.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:15 B:2 O:1
• Conservation: PhyloP100: 2.13
• Publications: 11 publications found

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

ENSG00000288208 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0199987).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128425.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUTYH	NM_001128425.2	MANE Plus Clinical	c.1508G>A	p.Gly503Glu	missense	Exon 15 of 16	NP_001121897.1
	MUTYH	NM_001048174.2	MANE Select	c.1424G>A	p.Gly475Glu	missense	Exon 15 of 16	NP_001041639.1
	MUTYH	NM_012222.3		c.1499G>A	p.Gly500Glu	missense	Exon 15 of 16	NP_036354.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUTYH	ENST00000710952.2	MANE Plus Clinical	c.1508G>A	p.Gly503Glu	missense	Exon 15 of 16	ENSP00000518552.2
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.1424G>A	p.Gly475Glu	missense	Exon 15 of 16	ENSP00000407590.2
	MUTYH	ENST00000372098.7	TSL:1	c.1499G>A	p.Gly500Glu	missense	Exon 15 of 16	ENSP00000361170.3

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152138 Hom.: 0 Cov.: 30

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

GnomAD2 exomes AF: 0.000132 AC: 32 AN: 243210 AF XY: 0.0000685

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000912

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.0000569 AC: 83 AN: 1457520 Hom.: 0 Cov.: 31 AF XY: 0.0000511 AC XY: 37 AN XY: 724584

African (AFR) AF: 0.00216 AC: 72 AN: 33388

American (AMR) AF: 0.0000452 AC: 2 AN: 44218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.00 AC: 0 AN: 85244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53184

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1109892

Other (OTH) AF: 0.0000664 AC: 4 AN: 60202

GnomAD4 genome AF: 0.000663 AC: 101 AN: 152256 Hom.: 0 Cov.: 30 AF XY: 0.000524 AC XY: 39 AN XY: 74452

African (AFR) AF: 0.00233 AC: 97 AN: 41554

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000694 Hom.: 0

Bravo AF: 0.000654

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000140 AC: 17

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:15 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial adenomatous polyposis 2 Uncertain:7

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 Breast or endometrial cancer (PMID: 25980754, 26689913, 35534704). 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.

Oct 07, 2024

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 22, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

Apr 13, 2016

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Aug 02, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Jan 26, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Jul 26, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 22, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2 Other:1

Jul 25, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 23, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

not provided Uncertain:2

Jan 06, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

Jun 19, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Gastric cancer;C3272841:Familial adenomatous polyposis 2 Uncertain:1

Mar 27, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MUTYH-related disorder Uncertain:1

Dec 15, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 23, 2024

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.020	T
MetaSVM	Uncertain	-0.072	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.1
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.27
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.015	D
Polyphen		0.78	P
Vest4		0.48
MVP		0.89
MPC		0.37
ClinPred		0.090	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.14
gMVP		0.32
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs3219494; hg19: chr1-45796198;