# HER2 (ERBB2) activating mutation

Source: https://onco.cc/biomarkers/her2-mutation/  
OnCo record `her2-mutation` (Biomarker). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

A HER2 mutation is a change in the gene's kinase domain, most often an exon 20 insertion, found in about 2 to 3 percent of lung adenocarcinomas. It is a different thing from HER2 amplification or overexpression, and it selects trastuzumab deruxtecan and, since 2025, zongertinib in lung cancer.

## Summary

Activating ERBB2 mutations cluster in the tyrosine kinase domain (exons 18 to 21), the commonest being the exon 20 insertion A775_G776insYVMA; they are detected by sequencing of tumour tissue or plasma. Trastuzumab deruxtecan's label covers unresectable or metastatic NSCLC whose tumours have activating HER2 (ERBB2) mutations in tumour or plasma specimens after prior systemic therapy (DESTINY-Lung02). Zongertinib (Hernexeos), approved in 2025, is labelled for non-squamous NSCLC with HER2 (ERBB2) tyrosine kinase domain activating mutations detected by an FDA-authorised test, testing plasma first and tissue if plasma is negative. The FDA list carries the Oncomine Dx Target Test and Guardant360 CDx for both drugs.

## Fields

- Kind: Biomarker
- Last checked: 2026-09-23
- Also known as: HER2 mutation; ERBB2 mutation; HER2-mutant NSCLC; ERBB2 exon 20 insertion; HER2 tyrosine kinase domain mutation; HER2 YVMA insertion; HER2 TKD mutation
- Tags: biomarker; her2

## Notes

- Gallbladder cancer: ERBB2 mutation without amplification in 4% of 260 patients, plus 1.5% with both and 0.4% fusion (Mondaca 2024); the extracellular S310F/Y hotspot predominated among Indian ERBB2 alterations (Suryavanshi 2025). These are not seen by IHC or ISH and fall outside the zanidatamab label; they were among the HER2-expressing or mutant tumours in the tumour-agnostic trastuzumab deruxtecan programme only where IHC was also positive.
- Lung cancer: exon 20 insertions in 1.9 to 2.2% of adenocarcinomas and 3.4% of never-smoker cases, with Y772_A775dup the dominant allele; any ERBB2 mutation reaches about 4% (cBioPortal; Kris 2014). This is the licensed HER2 readout in lung cancer, and it is separate from amplification and from immunohistochemistry, neither of which selects the oral HER2 inhibitors here. Kinase-domain missense variants (L755P, V777L, V842I) and the extracellular S310F are further separate classes not covered by the exon 20 indications.

## Sources

- ENHERTU prescribing information (DailyMed): https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e67e73e-ddf4-4e4d-8b50-09d7514910b6
- HERNEXEOS prescribing information (DailyMed): https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d3fabf12-354e-4e5c-b5de-20fdb579b783

## Connected records

- biomarkers: [EGFR exon 20 insertion](https://onco.cc/biomarkers/egfr-exon-20-insertion/), [HER2 IHC 3+ (HER2-positive by immunohistochemistry)](https://onco.cc/biomarkers/her2-ihc-3-plus/), [HER2 ISH amplified (ERBB2 gene amplification)](https://onco.cc/biomarkers/her2-ish-amplified/), [NRG1 gene fusion](https://onco.cc/biomarkers/nrg1-fusion/)
- cancers: [Gallbladder cancer](https://onco.cc/cancers/gallbladder/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- drugs: [Guardant360 CDx](https://onco.cc/drugs/guardant360-cdx/), [Oncomine Dx Target Test](https://onco.cc/drugs/oncomine-dx-target-test/), [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/), [Zongertinib](https://onco.cc/drugs/zongertinib/)
- terms: [EGFR exon 20 insertion](https://onco.cc/terms/egfr-exon20-insertion/), [HER2 testing in biliary tract cancer (IHC, ISH and NGS)](https://onco.cc/terms/her2-testing-in-biliary-cancer/), [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/)
- key papers: [Clinical and genomic characterization of ERBB2-altered gallbladder cancer: exploring differences between an American and a Chilean cohort](https://onco.cc/key-papers/paper-mondaca-erbb2-gallbladder-us-chile-jco-go-2024/), [Genomic and evolutionary classification of lung cancer in never smokers](https://onco.cc/key-papers/paper-zhang-lung-cancer-never-smokers-nat-genet-2021/), [Genomic profiling of Indian gallbladder carcinoma: mutational insights in a high-incidence population](https://onco.cc/key-papers/paper-suryavanshi-indian-gallbladder-genomics-jco-go-2025/), [Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs](https://onco.cc/key-papers/paper-kris-lung-cancer-mutation-consortium-jama-2014/)
- targets: [HER2](https://onco.cc/targets/her2/)

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