rs606231204

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_002354.3(EPCAM):c.499dupC(p.Gln167ProfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,454,666 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q167Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

EPCAM
NM_002354.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: -0.568

Publications

12 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 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 2-47377020-T-TC is Pathogenic according to our data. Variant chr2-47377020-T-TC is described in ClinVar as Pathogenic. ClinVar VariationId is 12774.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.499dupC	p.Gln167ProfsTer21	frameshift_variant	Exon 5 of 9	ENST00000263735.9	NP_002345.2	P16422

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EPCAM	ENST00000263735.9 link	c.499dupC	p.Gln167ProfsTer21	frameshift_variant	Exon 5 of 9	1	NM_002354.3	ENSP00000263735.4	P16422
EPCAM	ENST00000405271.5 link	c.583dupC	p.Gln195ProfsTer21	frameshift_variant	Exon 6 of 10	5		ENSP00000385476.1	B5MCA4
EPCAM	ENST00000456133.5 link	n.583dupC		non_coding_transcript_exon_variant	Exon 6 of 11	5		ENSP00000410675.1	B5MCA4
EPCAM	ENST00000490733.1 link	n.348dupC		non_coding_transcript_exon_variant	Exon 3 of 6	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1454666

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724276

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33330

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39644

South Asian (SAS)

AF:

0.00

AC:

AN:

86144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53350

Middle Eastern (MID)

AF:

0.000695

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105490

Other (OTH)

AF:

0.00

AC:

AN:

60142

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital diarrhea 5 with tufting enteropathy

Pathogenic:5

Feb 02, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Gln167ProfsX21 variant in EPCAM has been reported in >20 homozygous individuals and 2 compound heterozygous individuals with congenital diahrrea with tufting enteropathy and and segregated with disease in at least 1 affected individuals from 1 family. It is thought to be a founder mutation in the Gulf communities (Al-Mayouf 2009 PMID: 19820410, Salomon 2011 PMID: 21315192, Salomon 2014 PMID: 24142340, AlMahamed 2017 PMID: 28361844). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 12774). Immunohistochemistry on cases and controls showed no staining for EPCAM on the intercellular memebrane in individuals homozygous for the variant (Salomon 2011 PMID: 21315192, Schnell 2013 PMID: 23462293, Alfares 2017 PMID: 28454995). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 167 and leads to a premature termination codon 21 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the EPCAM gene is an established disease mechanism in autosomal recessive congenital diahrrea with tufting enteropathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive congenital diahrrea with tufting enteropathy. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2_Supporting, PP1, PS3_Supporting. -

May 02, 2018

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 08, 2023

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jul 05, 2024

Aleixo Muise Laboratory, Hospital For Sick Children

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

PVS1;PS1;PM2;PM3;PP3;PP4 -

not provided

Pathogenic:1

Dec 07, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect (Schnell et al., 2013); Not observed in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19820410, 21315192, 23462293, 28361844, 24142340, 28454995, 30202406, 30461124, 31462756, 32483295, 32735948) -

EPCAM-related disorder

Pathogenic:1

Jul 09, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The EPCAM c.499dupC variant is predicted to result in a frameshift and premature protein termination (p.Gln167Profs*21). This variant has been reported in the homozygous state in multiple consanguineous families with individuals presenting with congenital tufting enteropathy (Al-Mayouf et al. 2009. PubMed ID: 19820410; AlMahamed et al. 2017, PubMed ID: 28361844; Saloman et al. 2011. PubMed ID: 21315192, reported as c.498insC). Functional studies in vitro demonstrate that this variant leads to absent cell-surface EPCAM protein expression (Schnell et al. 2013, Figure 2. PubMed ID: 23462293). In addition, duodenal biopsy sections from patients homozygous for this variant are absent of intercellular staining of EPCAM (Saloman et al. 2011. PubMed ID: 21315192). This variant has not been reported in a large population database, and is reported in ClinVar as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/12774/). Frameshift variants in EPCAM are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.57

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over