CDH1
protein-codingcadherin 1, the group of CD molecules|Type I classical cadherins
Gene summary
This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]
- UVO
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~98.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0054740
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0010927
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0054740
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007338
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0100488
Submitter: ClinGen
*CDH1* encodes E-Cadherin, a classical cadherin of the cadherin superfamily, which functions to assist with calcium-dependent cell-cell adhesion to form organized tissues by complexing with catenins. There is abundant published evidence associating the *CDH1* gene with hereditary diffuse gastric cancer (DGC) since the gene-disease relationship was first proposed by Guilford et al. in 1998 (PMID: 9537325). Subsequently, evidence also reported an increase of risk of lobular breast cancer (LBC) in women. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern of above phenotypes; therefore, this curation includes both DGC and LBC. In 2022, to encompass the increased risk of both DGC and LBC, the ClinGen Disease Naming Committee and CDH1-VCEP have proposed a new disease entity as CDH1-related diffuse gastric and lobular breast cancer syndrome. The mechanism of pathogenicity is known to be loss-of-function. 13 variants (missense, nonsense, canonical splice site, and frameshift) that have been reported in 7 publications (PMIDs: 9537325, 10072428, 10433926, 12588804, 15831593, 19168852, 24366306) were included in this curation. The GCEP also evaluated emerging evidence (PMID: 34949788) suggesting an association of autosomal dominant colorectal cancer; however, this evidence was not scored since the GCEP identified the evidence as still preliminary. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease association is also supported by experimental evidence (6 points; PMIDs: 8236461, 9515965, 14500541, 2009537, 2070412). Loss of E-cadherin expression coincides with the transition from well differentiated adenoma to invasive carcinoma in a transgenic mouse model. Additionally, re-establishing the functional cadherin complex by expressing E-Cadherin in invasive epithelial tumor cell lines results in a reversion from an invasive to a benign epithelial phenotype. In summary, CDH1 is definitively associated with autosomal dominant CDH1-related diffuse gastric and lobular breast cancer syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene curation was approved by the ClinGen Hereditary Cancer GCEP on 03/22/2024 (SOP Version 10).
Inheritance Pattern: AD
Disease ID:MONDO:0007648
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0016419
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007339
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007648
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0100488
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0054740
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0054740
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0054740
Submitter: G2P
Inheritance Pattern: Unknown
Disease ID:MONDO:0016248
Submitter: ClinGen
Inheritance Pattern: AD
Disease ID:MONDO:0100488
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Dental; Gastrointestinal; Musculoskeletal; Oncologic
Intervention: Oncologic
Rationale: Surveillance and prophlyactic measures (which may include prophylactic gastrectomy) may allow early diagnosis and treatment (though there is controversy regarding the efficacy of prophlyaxis and surveillance measures), which may potentially be beneficial in the reduction of morbidity and mortality
Comments: Variants may also be involved in other malignancies (eg, prostate cancer) either as minor or major risk factors; Variants have also been implicated in the development of facial clefting
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CDH1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004360.5. 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 | 2 | 5 | 16 | 926 | 113 | 1062 |
| missense | 4 | 25 | 1913 | 557 | 27 | 2526 |
| nonsense | 114 | 14 | 6 | 134 | ||
| start loss | 5 | 1 | 2 | 8 | ||
| frameshift | 318 | 50 | 20 | 388 | ||
| splice donor/acceptor (+/-2bp) | 34 | 84 | 23 | 1 | 142 | |
| Total | 477 | 179 | 1980 | 1484 | 140 | 4260 |
Highest pathogenic variant AF is 0.000011717194
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004351.1 | 16 | MANE Select | |
| Ensembl | ENSP00000261769.4 | 16 | MANE Select | |
| RefSeq | NP_001304113.1 | 15 | Standard | |
| RefSeq | NP_001304114.1 | 7 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| cdh1 | Danio rerio | Structure: Rohon-Beard neuron Quality: mislocalised abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cell adhesion molecules (CAMs) - Homo sapiens (human)
- Gastric cancer - Homo sapiens (human)
- Adherens junction - Homo sapiens (human)
- Melanoma - Homo sapiens (human)
- Bladder cancer - Homo sapiens (human)
Biological Process
- cell morphogenesis
- cell-cell junction assembly
- homophilic cell adhesion via plasma membrane adhesion molecules
- synapse assembly
- response to toxic substance
Molecular Function
- calcium ion binding
- protein binding
- beta-catenin binding
- cytoskeletal protein binding
- ankyrin binding
Cellular Component
- extracellular region
- cytoplasm
- endosome
- trans-Golgi network
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000261769
- Coding exons
- 16
- Length
- 98324
- Individuals with no LoFs
- 125732
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 15
- Defined
- 125747
- p
- 0.0000596
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.706 | 448 | 492 | 0.910 | 0.0000299 | 5775 |
| Missense (PolyPhen) | 147 | 200.96 | 0.73149 | 2347 | ||
| Synonymous | 0.0918 | 200 | 202 | 0.992 | 0.0000143 | 1789 |
| Loss of Function | 4.22 | 9 | 36.5 | 0.246 | 0.00000202 | 432 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000053 | 0.000053 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Cadherins are calcium-dependent cell adhesion proteins (PubMed:11976333). They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. CDH1 is involved in mechanisms regulating cell-cell adhesions, mobility and proliferation of epithelial cells (PubMed:11976333). Has a potent invasive suppressor role. It is a ligand for integrin alpha-E/beta-7. {ECO:0000269|PubMed:11976333, ECO:0000269|PubMed:16417575}.;
- Disease
- DISEASE: Hereditary diffuse gastric cancer (HDGC) [MIM:137215]: A cancer predisposition syndrome with increased susceptibility to diffuse gastric cancer. Diffuse gastric cancer is a malignant disease characterized by poorly differentiated infiltrating lesions resulting in thickening of the stomach. Malignant tumors start in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. {ECO:0000269|PubMed:10319582, ECO:0000269|PubMed:12216071}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Heterozygous CDH1 germline mutations are responsible for familial cases of diffuse gastric cancer. Somatic mutations has also been found in patients with sporadic diffuse gastric cancer and lobular breast cancer.; DISEASE: Endometrial cancer (ENDMC) [MIM:608089]: A malignancy of endometrium, the mucous lining of the uterus. Most endometrial cancers are adenocarcinomas, cancers that begin in cells that make and release mucus and other fluids. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Ovarian cancer (OC) [MIM:167000]: The term ovarian cancer defines malignancies originating from ovarian tissue. Although many histologic types of ovarian tumors have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. {ECO:0000269|PubMed:8075649}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Breast cancer, lobular (LBC) [MIM:137215]: A type of breast cancer that begins in the milk-producing glands (lobules) of the breast. {ECO:0000269|PubMed:17660459}. Note=The gene represented in this entry may be involved in disease pathogenesis.; DISEASE: Blepharocheilodontic syndrome 1 (BCDS1) [MIM:119580]: A form of blepharocheilodontic syndrome, a rare autosomal dominant disorder. It is characterized by lower eyelid ectropion, upper eyelid distichiasis, euryblepharon, bilateral cleft lip and palate, and features of ectodermal dysplasia, including hair anomalies, conical teeth and tooth agenesis. An additional rare manifestation is imperforate anus. There is considerable phenotypic variability among affected individuals. {ECO:0000269|PubMed:28301459}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.934
Intolerance Scores
- LoFtool
- 0.329
- RVIS EVS
- -1.06
- RVIS percentile EVS
- 7.52
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.897
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |