1-45340256-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_025077.4(TOE1):c.4G>C(p.Ala2Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,628 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

TOE1
NM_025077.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 4.27

Publications

5 publications found

Variant links:

Genes affected

TOE1 (HGNC:15954): (target of EGR1, exonuclease) Enables poly(A)-specific ribonuclease activity and snRNA binding activity. Involved in RNA phosphodiester bond hydrolysis, exonucleolytic and snRNA 3'-end processing. Located in Cajal body and cytoplasm. Implicated in pontocerebellar hypoplasia type 7. [provided by Alliance of Genome Resources, Apr 2022]

TOE1 links:

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

MUTYH links:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOE1	NM_025077.4 link	c.4G>C	p.Ala2Pro	missense_variant	Exon 1 of 8	ENST00000372090.6	NP_079353.3
MUTYH	NM_001128425.2 link	c.-2C>G		5_prime_UTR_variant	Exon 1 of 16	ENST00000710952.2	NP_001121897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TOE1	ENST00000372090.6 link	c.4G>C	p.Ala2Pro	missense_variant	Exon 1 of 8	1	NM_025077.4	ENSP00000361162.5
MUTYH	ENST00000710952.2 link	c.-2C>G		5_prime_UTR_variant	Exon 1 of 16		NM_001128425.2	ENSP00000518552.2
ENSG00000288208	ENST00000671898.1 link	n.541-5745C>G		intron_variant	Intron 5 of 20			ENSP00000499896.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152240

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248736

AF XY:

0.00000740

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000892

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461388

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727014

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53010

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000719

AC:

AN:

1111990

Other (OTH)

AF:

0.0000331

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41472

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 2

Uncertain:2

Jul 21, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant occurs in a non-coding region of the MUTYH gene. It does not change the encoded amino acid sequence of the MUTYH protein. This variant is present in population databases (rs781609463, gnomAD 0.0009%). This variant has been observed in individual(s) with clinical features of MUTYH-related conditions (PMID: 28644590). ClinVar contains an entry for this variant (Variation ID: 619704). 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.

Hereditary cancer-predisposing syndrome

Uncertain:2

Jul 03, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.-2C>G variant is located in the 5' untranslated region (5’ UTR) of the MUTYH gene. This variant results from a C to G substitution 2 bases upstream from the first translated codon. This nucleotide position is highly conserved in available vertebrate species. This alteration, called a variant of unknown significance, has been reported in an Irish individual with approximately 12 colon polyps detected under the age of 50; this individual was also found to carry another MUTYH variant of unknown significance p.A419D (c.1256C>A) (McVeigh TP et al. Ir Med J, 2016 Dec;109:485). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Jun 07, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is located in the 5' untranslated region of the MUTYH gene. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a 49 year old individual affected with 12 polyps and carrying a second variant of uncertain significance, c.1256C>A (p.Ala419Asp). This variant has been identified in 1/248736 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 provided

Uncertain:1

Aug 30, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.079

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0084

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.54

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.66

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.9

PhyloP100

4.3

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.64

REVEL

Benign

0.26

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.62

ClinPred

0.97

GERP RS

5.0

PromoterAI

-0.57

Under-expression

(source)

Varity_R

0.44

gMVP

0.64

Mutation Taster

=66/34

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over