rs587781703

Variant names:

• chr1-45331792-G-A
• rs587781703
• NM_001128425.2:c.1055C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-45331792-G-A
• chr1-45331792-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001128425.2(MUTYH):​c.1055C>T​(p.Thr352Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. T352N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MUTYH NM_001128425.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 0.256
• Publications: 2 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10024902).

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.1055C>T	p.Thr352Ile	missense	Exon 12 of 16	NP_001121897.1
	MUTYH	NM_001048174.2	MANE Select	c.971C>T	p.Thr324Ile	missense	Exon 12 of 16	NP_001041639.1
	MUTYH	NM_012222.3		c.1046C>T	p.Thr349Ile	missense	Exon 12 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.1055C>T	p.Thr352Ile	missense	Exon 12 of 16	ENSP00000518552.2
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.971C>T	p.Thr324Ile	missense	Exon 12 of 16	ENSP00000407590.2
	MUTYH	ENST00000372098.7	TSL:1	c.1046C>T	p.Thr349Ile	missense	Exon 12 of 16	ENSP00000361170.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000809 AC: 2 AN: 247130 AF XY: 0.0000149

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460672 Hom.: 0 Cov.: 33 AF XY: 0.00000551 AC XY: 4 AN XY: 726544

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111418

Other (OTH) AF: 0.00 AC: 0 AN: 60320

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Aug 18, 2025

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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.

Jun 21, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with isoleucine at codon 352 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In an international breast cancer case-control meta-analysis, this variant was detected in 3/60466 cases and 2/53461 controls (PMID: 33471991). This variant has been identified in 2/247130 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.

Oct 12, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Familial adenomatous polyposis 2 Uncertain:2

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 threonine with isoleucine at codon 352 of the MUTYH protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In an international breast cancer case-control meta-analysis, this variant was detected in 3/60466 cases and 2/53461 controls (PMID: 33471991). This variant has been identified in 2/247130 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.

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 352 of the MUTYH protein (p.Thr352Ile). This variant is present in population databases (rs587781703, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 485903). 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 tolerated. 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.

not specified Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 11, 2025

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Aug 08, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MUTYH c.1055C>T (p.Thr352Ile) variant has been reported in the published literature in in individuals with breast cancer as well as in reportedly healthy individuals in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MUTYH)). The frequency of this variant in the general population, 0.0000081 (2/247130 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.26
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.080
Sift	Benign	0.032	D
Sift4G	Benign	0.11	T
Polyphen		0.0020	B
Vest4		0.17
MutPred		0.39		Loss of disorder (P = 0.0486)
MVP		0.36
MPC		0.14
ClinPred		0.071	T
GERP RS		-0.65
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.38
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs587781703; hg19: chr1-45797464;