EPCAM
protein-codingepithelial cell adhesion molecule, the group of CD molecules|MicroRNA protein coding host genes
Gene summary
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]
- M4S1
- MIC18
- TACSTD1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~42.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013196
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013184
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013184
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013184
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013196
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0005835
Submitter: ClinGen
EPCAM was first reported in relation to autosomal dominant Lynch Syndrome (MONDO:0005835) in 2009 by two publications (Ligtenberg MJ et al., PMID:19098912 and Kovacs ME et. al. PMID:19177550). EPCAM deletions involved in Lynch Syndrome are also frequently described in literature as associated with Hereditary Non-Polyposis Colorectal Cancer 8 (HNPCC8, MONDO:0013196) a similar disorder. Five variants, all large deletions spanning the 8th and 9th exon of EPCAM into the intergenic region prior to the MSH2 promoter, reported in 6 probands across 3 publications were curated. Many additional publications describe similar deletions in tumor sequencing cohorts. However, the maximum score for genetic evidence has been reached (12 points). The EPCAM deletions spanning the 8th and 9th exon and intergenic space cause hypermethylation at the MSH2 promoter, which causes a decrease or complete loss of MSH2 expression. It is important to note that loss of the EPCAM gene itself has not been definitively associated with Lynch Syndrome / HNPCC8. Complete absence of EPCAM protein expression through recessive truncating mutations causes an apparently unrelated syndrome – congenital tufting enteropathy. EPCAM protein expression or absence does not bear literature evidence in isolation to support a causal role in Lynch Syndrome / HNPCC8 in the absence of disruption of MSH2. The specific deletions spanning EPCAM into the intergenic space of MSH2 are a distinct mutation type with promoter methylation regulatory effects on MSH2 expression. This gene-disease association is also supported by experimental evidence (2.5 points) showing EPCAM tissue expression in glandular cells of glandular cells of the duodenum, small intestine, colon and rectum (though not expressed in the endothelial cells of the colon), as well as MSH2 immunohistochemistry assays showing loss of MSH2 expression with EPCAM deletions, and promoter hypermethylation in cells carrying these characteristic deletions (PMIDs: 24309898, 19177550, 19098912). In summary, EPCAM deletions spanning the last exons of EPCAM to the intergenic region prior to MSH2 promoter are definitively associated (14.5 points) with Lynch Syndrome / HNPCC8. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0013184
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0013196
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0005835
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013184
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0016419
Submitter: ClinGen
EPCAM (Epithelial cell adhesion molecule) is a transmembrane glycoprotein mediating Calcium-independent homotypic cell–cell adhesion in epithelia. EPCAM is also involved in multiple cellular events including cell migration, proliferation, and differentiation. Deletions of *EPCAM* that silence nearby *MSH2* has been linked to autosomal dominant Lynch Syndrome, which was curated separately. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, curations to refute or dispute can be split when needed. This curation focuses on refuting the association with breast cancer. Evidence curated in this gene-disease relationship includes case-control data and experimental data. **Summary of Case-Control Data: 0 point** This gene-disease relationship has been studied in at least 1 large case-control studies at the aggregate level in 2021 [BCAC (PMID: 33471991) with more than 48 thousand cases and controls] did not identify a significant association of aggregate loss of function (LOF) variants in *EPCAM* and breast cancer. **Summary of Experimental Data: 0 point** There is experimental evidence showing that knockdown of *EPCAM* in breast cell lines has variable effects on cell proliferation, in which some cell lines showed low growth and others showed high growth. Another study reported that EPCAM is expressed in human breast epithelium and human ovarian epithelium. However, since the experimental evidence is not specific and conclusive, no point was awarded. **Overall Summary:** In summary, given the lack of significant association in large breast cancer case-control studies to date, there is convincing evidence refuting the association between *EPCAM* and autosomal dominant hereditary breast cancer, which significantly outweighs the evidence supporting the association. This gene-disease pair was originally evaluated as no known disease relationship by the Breast/Ovarian Cancer GCEP on 4/12/2017. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 6/9/2023 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0013196
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Gastrointestinal; Musculoskeletal; Oncologic
Intervention: Gastrointestinal; Oncologic
Rationale: In HNPCC, for surveillance, colonoscopy with polyp removal is indicated starting at (whichever is earlier) age 20-25 years or 10 years prior to the earliest familial diagnosis; Prophylactic Hysterectomy with bilateral oophorectomy may be considered after childbearing is completed; For individuals with colon cancer, surgical treatment with full colectomy (and ileorectal anastomosis) is recommended; Cigarette smoking should be avoided; For other tumor types, awareness of cancer risk may allow early diagnosis and treatment, which may reduce morbidity and mortality; In Diarrhea 5, with tufting enteropathy, congenital, most affected individuals require parenteral nutrition for normal growth and development, and awareness can allow prompt medical/nutritional support
Comments: Specific deletions result in MSH2 inactivation; Although Colorectal cancer, hereditary nonpolyposis, type 8 typically manifests in adulthood, individuals have been reported such that familial screening would be recommended to commence during the pediatric period; Diarrhea 5, with tufting enteropathy, congenital may include additional features, such as dysmorphism
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to EPCAM variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002354.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 233 | 234 | |||
| missense | 1 | 3 | 524 | 30 | 6 | 564 |
| nonsense | 12 | 3 | 15 | |||
| start loss | 1 | 2 | 1 | 4 | ||
| frameshift | 11 | 5 | 2 | 18 | ||
| splice donor/acceptor (+/-2bp) | 11 | 4 | 7 | 22 | ||
| Total | 36 | 17 | 535 | 263 | 6 | 857 |
Highest pathogenic variant AF is 0.00009534838
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002345.2 | 9 | MANE Select | |
| Ensembl | ENSP00000263735.4 | 9 | MANE Select | |
| Ensembl | ENSP00000385476.1 | 9 | Standard | |
| Ensembl | ENSP00000385476.1 | 9 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| epcam | Danio rerio | Structure: keratinocyte Quality: aggregated abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cell surface interactions at the vascular wall
- Hemostasis
Biological Process
- ureteric bud development
- positive regulation of cell population proliferation
- signal transduction involved in regulation of gene expression
- positive regulation of transcription by RNA polymerase II
- stem cell differentiation
Molecular Function
- protein binding
- protein-containing complex binding
- cadherin binding involved in cell-cell adhesion
Cellular Component
- plasma membrane
- bicellular tight junction
- cell surface
- integral component of membrane
- basolateral plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000263735
- Coding exons
- 9
- Length
- 42444
- Individuals with no LoFs
- 125706
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 42
- Defined
- 125748
- p
- 0.000167
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -1.43 | 219 | 167 | 1.31 | 0.00000827 | 2059 |
| Missense (PolyPhen) | 65 | 51.667 | 1.258 | 654 | ||
| Synonymous | -1.65 | 75 | 58.9 | 1.27 | 0.00000311 | 580 |
| Loss of Function | 1.06 | 13 | 17.8 | 0.729 | 9.93e-7 | 212 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00038 | 0.00038 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00016 | 0.00016 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0.00036 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: May act as a physical homophilic interaction molecule between intestinal epithelial cells (IECs) and intraepithelial lymphocytes (IELs) at the mucosal epithelium for providing immunological barrier as a first line of defense against mucosal infection. Plays a role in embryonic stem cells proliferation and differentiation. Up-regulates the expression of FABP5, MYC and cyclins A and E. {ECO:0000269|PubMed:15195135, ECO:0000269|PubMed:15922867, ECO:0000269|PubMed:19785009, ECO:0000269|PubMed:20064925}.;
- Disease
- DISEASE: Diarrhea 5, with tufting enteropathy, congenital (DIAR5) [MIM:613217]: An intractable diarrhea of infancy characterized by villous atrophy and absence of inflammation, with intestinal epithelial cell dysplasia manifesting as focal epithelial tufts in the duodenum and jejunum. {ECO:0000269|PubMed:18572020}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hereditary non-polyposis colorectal cancer 8 (HNPCC8) [MIM:613244]: An autosomal dominant disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early-onset colorectal carcinoma (CRC) and extra-colonic tumors of the gastrointestinal, urological and female reproductive tracts. HNPCC is reported to be the most common form of inherited colorectal cancer in the Western world. Clinically, HNPCC is often divided into two subgroups. Type I is characterized by hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II is characterized by increased risk for cancers in certain tissues such as the uterus, ovary, breast, stomach, small intestine, skin, and larynx in addition to the colon. Diagnosis of classical HNPCC is based on the Amsterdam criteria: 3 or more relatives affected by colorectal cancer, one a first degree relative of the other two; 2 or more generation affected; 1 or more colorectal cancers presenting before 50 years of age; exclusion of hereditary polyposis syndromes. The term 'suspected HNPCC' or 'incomplete HNPCC' can be used to describe families who do not or only partially fulfill the Amsterdam criteria, but in whom a genetic basis for colon cancer is strongly suspected. {ECO:0000269|PubMed:19098912}. Note=The disease is caused by mutations affecting the gene represented in this entry. HNPCC8 results from heterozygous deletion of 3-prime exons of EPCAM and intergenic regions directly upstream of MSH2, resulting in transcriptional read-through and epigenetic silencing of MSH2 in tissues expressing EPCAM.;
Recessive Scores
- pRec
- 0.295
Intolerance Scores
- LoFtool
- 0.719
- RVIS EVS
- 0.37
- RVIS percentile EVS
- 75.29
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.211
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |