ERBB2
Chr 17ARerb-b2 receptor tyrosine kinase 2
Also known as: CD340, HER-2, HER-2/neu, HER2, MLN 19, MLN-19, NEU, NGL
The protein is a receptor tyrosine kinase that forms heterodimers with other EGF receptor family members to activate downstream signaling pathways and regulates microtubule stabilization at the cell periphery. Mutations cause autosomal dominant developmental delays, intellectual disability, and growth abnormalities as part of a neurodevelopmental syndrome. The gene is highly constrained against loss-of-function variants (LOEUF 0.397), indicating that haploinsufficiency is likely not tolerated in the general population.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Highly missense-constrained (top ~0.1%)
This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
400 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 4 | 2 | 0 | 6 |
Likely Pathogenic | 0 | 0 | 0 | 0 | 0 |
VUS | 13 | 187 | 7 | 3 | 210 |
Likely Benign | 0 | 2 | 66 | 79 | 147 |
Benign | 0 | 0 | 5 | 0 | 5 |
Conflicting | — | 4 | |||
| Total | 13 | 193 | 80 | 82 | 372 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
ERBB2 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Testing Trastuzumab and Pertuzumab in Patients With Higher Than Normal Copies of the HER2 Gene Found in Their Tumors (MATCH - Subprotocol J)
ACTIVE NOT RECRUITINGDDR Genes Alteration and Response to Platinum-based Chemotherapy in Advanced Urothelial Cancer.
RECRUITINGStudy of RGT-490 in Patients With PIK3CA-Mutated Advanced Solid Tumors
RECRUITINGElacestrant With/Without Triptorelin in Premenopausal Women With Luminal Breast Cancer
RECRUITINGBeamion LUNG-1: A Study to Test Different Doses of Zongertinib in People With Different Types of Advanced Cancer (Solid Tumours With Changes in the HER2 Gene)
ACTIVE NOT RECRUITINGPalbociclib in Metastatic Breast Cancer: Gene Polymorphism-based Study in Egyptian Patients.
NOT YET RECRUITINGSafety and Immune Response to a Mammaglobin-A DNA Vaccine In Breast Cancer Patients Undergoing Neoadjuvant Endocrine Therapy
ACTIVE NOT RECRUITINGEvaluate BL-M17D1 in Patients w/HER2-Expressing/Mutant Advanced or Metastatic Solid Tumors
ACTIVE NOT RECRUITINGStudy of Oral MRT-2359 in Selected Cancer Patients
ACTIVE NOT RECRUITINGClinical Study of Camrelizumab Combined With TCb Versus TCb in Neoadjuvant Treatment of Triple-negative Breast Cancer
RECRUITINGNeoadjuvant Concomitant Modulated Electro-hyperthermia in HER2-negative Breast Cancer
ACTIVE NOT RECRUITINGPreoperative Fulvestrant With or Without Enzalutamide in ER+/Her2- Breast Cancer
ACTIVE NOT RECRUITINGExternal Resources
Links to major genomics databases and tools