2-47373967-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002354.3(EPCAM):c.344T>C(p.Met115Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.478 in 1,613,628 control chromosomes in the GnomAD database, including 193,996 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M115I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.58 ( 27738 hom., cov: 31)

Exomes 𝑓: 0.47 ( 166258 hom. )

Consequence

EPCAM
NM_002354.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.0500

Publications

77 publications found

Variant links:

Genes affected

EPCAM (HGNC:11529): (epithelial cell adhesion molecule) This gene encodes a carcinoma-associated antigen and is a member of a family that includes at least two type I membrane proteins. This antigen is expressed on most normal epithelial cells and gastrointestinal carcinomas and functions as a homotypic calcium-independent cell adhesion molecule. The antigen is being used as a target for immunotherapy treatment of human carcinomas. Mutations in this gene result in congenital tufting enteropathy. [provided by RefSeq, Dec 2008]

EPCAM Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Lynch syndrome 8
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
congenital diarrhea 5 with tufting enteropathy
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, G2P, Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

EPCAM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.3098158E-6).

BP6

Variant 2-47373967-T-C is Benign according to our data. Variant chr2-47373967-T-C is described in ClinVar as Benign. ClinVar VariationId is 183700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPCAM	NM_002354.3 link	c.344T>C	p.Met115Thr	missense_variant	Exon 3 of 9	ENST00000263735.9	NP_002345.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPCAM	ENST00000263735.9 link	c.344T>C	p.Met115Thr	missense_variant	Exon 3 of 9	1	NM_002354.3	ENSP00000263735.4

Frequencies

GnomAD3 genomes

AF:

0.577

AC:

87547

AN:

151766

Hom.:

27689

Cov.:

show subpopulations

Gnomad AFR

AF:

0.831

Gnomad AMI

AF:

0.354

Gnomad AMR

AF:

0.494

Gnomad ASJ

AF:

0.363

Gnomad EAS

AF:

0.817

Gnomad SAS

AF:

0.498

Gnomad FIN

AF:

0.591

Gnomad MID

AF:

0.361

Gnomad NFE

AF:

0.443

Gnomad OTH

AF:

0.526

GnomAD2 exomes

AF:

0.513

AC:

129014

AN:

251424

AF XY:

0.501

show subpopulations

Gnomad AFR exome

AF:

0.842

Gnomad AMR exome

AF:

0.472

Gnomad ASJ exome

AF:

0.363

Gnomad EAS exome

AF:

0.832

Gnomad FIN exome

AF:

0.596

Gnomad NFE exome

AF:

0.436

Gnomad OTH exome

AF:

0.464

GnomAD4 exome

AF:

0.467

AC:

683281

AN:

1461744

Hom.:

166258

Cov.:

AF XY:

0.466

AC XY:

338676

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.849

AC:

28436

AN:

33480

American (AMR)

AF:

0.474

AC:

21210

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.368

AC:

9609

AN:

26134

East Asian (EAS)

AF:

0.790

AC:

31354

AN:

39700

South Asian (SAS)

AF:

0.480

AC:

41378

AN:

86258

European-Finnish (FIN)

AF:

0.592

AC:

31632

AN:

53414

Middle Eastern (MID)

AF:

0.383

AC:

2208

AN:

5768

European-Non Finnish (NFE)

AF:

0.438

AC:

487525

AN:

1111880

Other (OTH)

AF:

0.496

AC:

29929

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

20970

41939

62909

83878

104848

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14996

29992

44988

59984

74980

<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:

0.577

AC:

87649

AN:

151884

Hom.:

27738

Cov.:

AF XY:

0.582

AC XY:

43171

AN XY:

74194

show subpopulations

African (AFR)

AF:

0.831

AC:

34451

AN:

41454

American (AMR)

AF:

0.494

AC:

7513

AN:

15214

Ashkenazi Jewish (ASJ)

AF:

0.363

AC:

1262

AN:

3472

East Asian (EAS)

AF:

0.816

AC:

4214

AN:

5164

South Asian (SAS)

AF:

0.498

AC:

2400

AN:

4820

European-Finnish (FIN)

AF:

0.591

AC:

6210

AN:

10504

Middle Eastern (MID)

AF:

0.361

AC:

106

AN:

294

European-Non Finnish (NFE)

AF:

0.442

AC:

30066

AN:

67946

Other (OTH)

AF:

0.525

AC:

1105

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1667

3334

5001

6668

8335

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

702

1404

2106

2808

3510

<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:

0.480

Hom.:

63144

Bravo

AF:

0.580

TwinsUK

AF:

0.446

AC:

1654

ALSPAC

AF:

0.435

AC:

1676

ESP6500AA

AF:

0.828

AC:

3649

ESP6500EA

AF:

0.433

AC:

3722

ExAC

AF:

0.520

AC:

63080

Asia WGS

AF:

0.658

AC:

2287

AN:

3478

EpiCase

AF:

0.422

EpiControl

AF:

0.412

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27153395, 20683652, 22322561) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital diarrhea 5 with tufting enteropathy

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lynch syndrome 1

Benign:1

Aug 18, 2017

IntelligeneCG

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lynch syndrome 8

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Jan 16, 2013

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: 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.040

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.0039

T;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.018

.;T;T

MetaRNN

Benign

0.0000033

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.4

.;N;.

PhyloP100

0.050

PrimateAI

Benign

0.31

PROVEAN

Benign

2.2

N;N;N

REVEL

Benign

0.18

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.020

MPC

0.013

ClinPred

0.0024

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.36

Mutation Taster

=97/3

polymorphism (auto)

(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