2-47378939-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_002354.3(EPCAM):c.556-14A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000953 in 1,153,664 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

EPCAM
NM_002354.3 intron

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: -0.0690

Publications

16 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: Pathogenic. The variant received 10 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 2-47378939-A-G is Pathogenic according to our data. Variant chr2-47378939-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 157603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPCAM	NM_002354.3 link	c.556-14A>G		intron_variant	Intron 5 of 8	ENST00000263735.9	NP_002345.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
EPCAM	ENST00000263735.9 link	c.556-14A>G	intron_variant	Intron 5 of 8	1	NM_002354.3	ENSP00000263735.4
EPCAM	ENST00000405271.5 link	c.640-14A>G	intron_variant	Intron 6 of 9	5		ENSP00000385476.1
EPCAM	ENST00000456133.5 link	n.640-14A>G	intron_variant	Intron 6 of 10	5		ENSP00000410675.1
EPCAM	ENST00000490733.1 link	n.405-14A>G	intron_variant	Intron 3 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000764

AC:

AN:

248832

AF XY:

0.0000964

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000107

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000105

AC:

105

AN:

1001604

Hom.:

Cov.:

AF XY:

0.000104

AC XY:

AN XY:

518722

show subpopulations

African (AFR)

AF:

0.0000407

AC:

AN:

24592

American (AMR)

AF:

0.0000227

AC:

AN:

44098

Ashkenazi Jewish (ASJ)

AF:

0.000172

AC:

AN:

23258

East Asian (EAS)

AF:

0.0000801

AC:

AN:

37442

South Asian (SAS)

AF:

0.000118

AC:

AN:

76578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52950

Middle Eastern (MID)

AF:

0.000234

AC:

AN:

4266

European-Non Finnish (NFE)

AF:

0.000124

AC:

AN:

693402

Other (OTH)

AF:

0.00

AC:

AN:

45018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

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:

0.0000329

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74260

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41396

American (AMR)

AF:

0.000131

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.585

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:

0.0000215

Hom.:

Bravo

AF:

0.0000491

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital diarrhea 5 with tufting enteropathy

Pathogenic:10

Jul 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Oct 10, 2016

ITMI

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Dec 28, 2021

Genomics Facility, Ludwig-Maximilians-Universität München

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 17, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was identified as homozygous

Aug 02, 2023

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The EPCAM c.556-14A>G intronic change results in an A to G substitution at the -14 position of intron 5 of the EPCAM gene. Algorithms that predict the impact of sequence changes on splicing indicate that this change results in the creation of a splice acceptor site, which is predicted to cause a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of protein due to nonsense-mediated decay. This variant has been reported in multiple individuals with congenital tufting enteropathy in the homozygous and compound heterozygous state (PMID: 23462293, 24142340, 26684320, 27848944, 28701297, 30461124). This variant has a maximum subpopulation frequency of 0.013% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). In summary, this variant meets criteria to be classified as pathogenic with respect to congenital tufting enteropathy and of uncertain significance with respect to Lynch syndrome since the evidence currently available is insufficient to determine the clinical significance of this variant with respect to Lynch syndrome.

Aug 30, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.556-14A>G variant in EPCAM has been reported in 10 individuals with congenital tufting enteropathy, at least 3 of which were homozygous or had additional variants in EPCAM (Schnell 2013 PMID: 23462293, Salomon 2014 PMID: 24142340, Bodian 2017 PMID: 28701297). One of these individuals had absence of EPCAM cell surface expression (Bodian 2017 PMID: 28701297). It segregated with disease in 2 affected family members from 2 families (Salomon 2014 PMID: 24142340, Bodian 2017 PMID: 28701297). It has also been identified in 0.02% (1/5192) of East Asian and 0.01% (1/15268) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 157603). Studies have shown that this intronic variant creates a new acceptor site within intron 5, which is predicted to create a framshift variant p.Tyr186PhefsX6. Studies have also shown that this variant causes loss of cell-surface EpCAM (Schnell 2013 PMID: 23462293, Salomon 2014 PMID: 24142340). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive congenital tufting enteropathy. ACMG/AMP Criteria applied: PM3, PS3, PP1_Moderate.

Oct 29, 2024

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.010%). Predicted Consequence/Location: Intron variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 23462293). In silico tools predict the variant to alter splicing and produce an abnormal transcript [SpliceAI: 0.96 (>=0.2, moderate evidence for spliceogenicity)]. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 23462293, 24142340). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000157603 /PMID: 23462293 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Jul 06, 2022

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Suma Genomics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 10, 2025

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:3

Dec 28, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 34426522, 33195669, 24142340, 36457962, 23462293, 34198699, 29978187, 36451688, 26684320, 30461124, 33029133, 37554749, 27848944, 28701297, 33567694, 35261632)

Jan 10, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In cDNA sequence analysis using patient-derived RNA, this variant resulted in a frameshift caused by abnormal splicing (PMID: 24142340). An experimental study using cells expressing the truncated protein (p.Tyr186Phefs*6) has shown that this truncated protein lacks the transmembrane domain of EPCAM, resulting in loss of cell-surface EPCAM protein, and reduced protein secretion in vitro (PMID: 23462293). For these reasons, this variant has been classified as Pathogenic. This variant has been reported in multiple individuals affected with congenital tufting enteropathy (CTE)¬†(PMID: 23462293, 24142340, 28701297). ClinVar contains an entry for this variant (Variation ID: 157603). This variant is present in population databases (rs376155665, ExAC 0.01%). This sequence change falls in intron 5 of the EPCAM mRNA. It has been shown to affect mRNA splicing through the creation of new splice acceptor site, which causes a frameshift at codon 186 and creates a premature translational stop signal (p.Tyr186Phefs*6) (PMID: 23462293, 24142340). It is expected to result in an absent or disrupted protein product.

Sep 19, 2024

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Lynch syndrome 8;C2750737:Congenital diarrhea 5 with tufting enteropathy

Pathogenic:1

May 25, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

EPCAM-related disorder

Pathogenic:1

May 23, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The EPCAM c.556-14A>G variant is predicted to interfere with splicing. This variant has been reported in the homozygous and compound heterozygous state in patients with congenital tufting enteropathy (Schnell et al. 2013. PubMed ID: 23462293; Salomon et al. 2013. PubMed ID: 24142340; Bodian et al. 2017. PubMed ID: 28701297; Ayyıldız Civan et al. 2021. PubMed ID: 34198699) and in at least one study it was found to be associated with milder outcomes (Salomon et al. 2013. PubMed ID: 24142340). Transcript analysis found this variant results in abnormal splicing (Salomon et al. 2013. PubMed ID: 24142340) and immunostaining found it results in a lack of cell surface expression (Schnell et al. 2013. PubMed ID: 23462293). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD and has been interpreted as pathogenic/likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/157603/). This variant is interpreted as pathogenic.

Familial cancer of breast

Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Uncertain

(source)

DANN

Benign

0.56

PhyloP100

-0.069

Mutation Taster

=40/60

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.96

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.96

Position offset: 1

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