EGFR
protein-codingepidermal growth factor receptor, the group of Erb-b2 receptor tyrosine kinases
Gene summary
The protein encoded by this gene is a transmembrane glycoprotein that is a member of the protein kinase superfamily. This protein is a receptor for members of the epidermal growth factor family. EGFR is a cell surface protein that binds to epidermal growth factor, thus inducing receptor dimerization and tyrosine autophosphorylation leading to cell proliferation. Mutations in this gene are associated with lung cancer. EGFR is a component of the cytokine storm which contributes to a severe form of Coronavirus Disease 2019 (COVID-19) resulting from infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). [provided by RefSeq, Jul 2020]
- ERBB
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~192.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008903
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0014481
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014481
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0014481
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0008903
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014481
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014481
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0005233
Submitter: ClinGen
Activating missense and inframe deletion variants in the tyrosine kinase domain of EGFR are commonly reported in pre-treatment tumoral tissue analyses of individuals with non-small cell lung cancer. The relationship of germline variants in EGFR to autosomal dominant familial non-small cell lung cancer, adenocarcinoma subtype, was first reported in 2005 (Bell DW et al., PMIDs: 16258541). Two variants that have been reported in germline of twelve probands in eleven literature (PMIDs: 24736066, 16258541, 20068085, 20068085, 21252721, 22588155, 24736080, 18355544, 21172876, 23380224, 25176975, 23358982) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (7 pts.) has been reached. The mechanism for disease is gain-of-function. This gene-disease association is particularly supported for p.T790M germline variant by the number of families, animal models and in vitro functional assays on cell culture models where it has been shown to confer oncogenic properties such as tumor development and increased colony formation (PMIDs: 17726540, 17671201). There is also limited experimental evidence for p.V843I showing increased colony formation (PMID:25057940). In summary, EGFR is definitively associated with autosomal dominant familial non-small cell lung cancer susceptibility [MIM:211980]. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Lumping and Splitting: Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found difference in molecular mechanisms (gain of function versus loss of function), inheritance pattern, and phenotypic variability between Non-small cell lung cancer, susceptibility to [MIM:211980] and Inflammatory skin and bowel disease, neonatal, 2 [MIM:616069]. Additionally, no cancer has been reported in both biallelic and monoallelic loss-of-function variant carriers.
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Cardiovascular
Intervention: Allergy/Immunology/Infectious; Cardiovascular
Rationale: In Inflammatory skin and bowel disease, neonatal, 2, antiinfectious prophylaxis andearly and aggressive treatment of infections may be beneficial, and individuals may also have cardiovascular manifestations such that surveillance may allow beneficial interventions
Comments: In familial AML, one family has been reported, in which there was an inherited genomic ERBB rearrangement
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to EGFR variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005228.5. 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 | 30 | 955 | 13 | 998 | ||
| missense | 13 | 15 | 1792 | 212 | 2 | 2034 |
| nonsense | 14 | 15 | 19 | 48 | ||
| start loss | 0 | |||||
| frameshift | 29 | 4 | 28 | 1 | 62 | |
| splice donor/acceptor (+/-2bp) | 34 | 25 | 59 | |||
| Total | 56 | 68 | 1894 | 1168 | 15 | 3201 |
Highest pathogenic variant AF is 0.000019710647
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005219.2 | 28 | MANE Select | |
| Ensembl | ENSP00000275493.2 | 28 | MANE Select | |
| RefSeq | NP_001333826.1 | 26 | Standard | |
| RefSeq | NP_001333827.1 | 27 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| egfra | Danio rerio | Structure: dorsal aorta Quality: decreased diameter abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- Non-small cell lung cancer - Homo sapiens (human)
- Gastric cancer - Homo sapiens (human)
- Focal adhesion - Homo sapiens (human)
- Relaxin signaling pathway - Homo sapiens (human)
Biological Process
- MAPK cascade
- activation of MAPKK activity
- ossification
- embryonic placenta development
- positive regulation of protein phosphorylation
Molecular Function
- virus receptor activity
- chromatin binding
- double-stranded DNA binding
- MAP kinase kinase kinase activity
- protein tyrosine kinase activity
Cellular Component
- Golgi membrane
- extracellular space
- nucleus
- cytoplasm
- endosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000275493
- Coding exons
- 28
- Length
- 237600
- Individuals with no LoFs
- 125726
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 22
- Defined
- 125748
- p
- 0.0000875
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.87 | 561 | 701 | 0.801 | 0.0000445 | 8006 |
| Missense (PolyPhen) | 203 | 324.57 | 0.62544 | 3634 | ||
| Synonymous | -1.65 | 315 | 280 | 1.13 | 0.0000199 | 2270 |
| Loss of Function | 5.83 | 15 | 66.2 | 0.226 | 0.00000373 | 742 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00019 | 0.00018 | rare |
| Latino/Admixed American | 0.000087 | 0.000087 | rare |
| Ashkenazi Jewish | 0.00020 | 0.00020 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00011 | 0.00011 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses (PubMed:2790960, PubMed:10805725, PubMed:27153536). Known ligands include EGF, TGFA/TGF-alpha, AREG, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF (PubMed:2790960, PubMed:7679104, PubMed:8144591, PubMed:9419975, PubMed:15611079, PubMed:12297049, PubMed:27153536, PubMed:20837704). Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS- RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules (PubMed:27153536). May also activate the NF-kappa-B signaling cascade (PubMed:11116146). Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling (PubMed:11602604). Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin (PubMed:11483589). Plays a role in enhancing learning and memory performance (By similarity). {ECO:0000250|UniProtKB:Q01279, ECO:0000269|PubMed:10805725, ECO:0000269|PubMed:11116146, ECO:0000269|PubMed:11483589, ECO:0000269|PubMed:11602604, ECO:0000269|PubMed:12297049, ECO:0000269|PubMed:12297050, ECO:0000269|PubMed:12620237, ECO:0000269|PubMed:12873986, ECO:0000269|PubMed:15374980, ECO:0000269|PubMed:15590694, ECO:0000269|PubMed:15611079, ECO:0000269|PubMed:17115032, ECO:0000269|PubMed:19560417, ECO:0000269|PubMed:20837704, ECO:0000269|PubMed:21258366, ECO:0000269|PubMed:27153536, ECO:0000269|PubMed:2790960, ECO:0000269|PubMed:7679104, ECO:0000269|PubMed:8144591, ECO:0000269|PubMed:9419975}.; FUNCTION: (Microbial infection) Acts as a receptor for hepatitis C virus (HCV) in hepatocytes and facilitates its cell entry. Mediates HCV entry by promoting the formation of the CD81-CLDN1 receptor complexes that are essential for HCV entry and by enhancing membrane fusion of cells expressing HCV envelope glycoproteins. {ECO:0000269|PubMed:21516087}.;
- Disease
- DISEASE: Lung cancer (LNCR) [MIM:211980]: A common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. {ECO:0000269|PubMed:15118125, ECO:0000269|PubMed:16533793, ECO:0000269|PubMed:16672372}. Note=The gene represented in this entry is involved in disease pathogenesis.; DISEASE: Inflammatory skin and bowel disease, neonatal, 2 (NISBD2) [MIM:616069]: A disorder characterized by inflammatory features with neonatal onset, involving the skin, hair, and gut. The skin lesions involve perioral and perianal erythema, psoriasiform erythroderma, with flares of erythema, scaling, and widespread pustules. Gastrointestinal symptoms include malabsorptive diarrhea that is exacerbated by intercurrent gastrointestinal infections. The hair is short or broken, and the eyelashes and eyebrows are wiry and disorganized. {ECO:0000269|PubMed:24691054}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.989
Intolerance Scores
- LoFtool
- 0.0455
- RVIS EVS
- -2.16
- RVIS percentile EVS
- 1.44
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.996
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |