# BRAF class II and class III mutations (non-V600)

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

## TL;DR

Class II and III BRAF mutations sit outside codon 600 and signal as pairs (class II) or by leaning on RAS (class III). Approved BRAF inhibitors do not work on them, and no drug is yet approved for them; pan-RAF inhibitors are in trials.

## Summary

Class II mutations (K601E, G469A, L597 and others, plus fusions and in-frame deletions) form RAS-independent dimers; class III mutations (D594, G466, N581) are kinase-impaired and amplify upstream RAS or receptor signalling. Neither responds to the monomer-selective inhibitors vemurafenib, dabrafenib or encorafenib, and the labels state the drugs are not indicated for BRAF wild-type tumours without addressing these classes. No approval exists: tovorafenib, a type II RAF inhibitor, is approved only for paediatric low-grade glioma with BRAF fusion or V600 mutation, and trials of pan-RAF inhibitors and MEK inhibitors (for example the NCI-MATCH sub-protocol of trametinib for non-V600 BRAF, and the tovorafenib FIREFLY-2 programme) define the group. The classification is from Yao et al. (Cancer Cell 2015, Nature 2017).

## Fields

- Kind: Biomarker
- Last checked: 2026-09-23
- Also known as: BRAF class II; BRAF class III; non-V600 BRAF; BRAF K601E; BRAF G469A; BRAF D594G; atypical BRAF mutation; BRAF non-V600E
- Tags: biomarker; braf; no-approval

## Notes

- Colorectal cancer: non-V600 BRAF mutations occurred in 208 of 9,643 sequenced metastatic patients (2.2%) and accounted for 22% of all BRAF mutations. They define a clinically distinct group: younger (median 58 against 68 years), less often female, lower grade, less often right-sided, and with median overall survival of 60.7 months against 11.4 for V600E and 43.0 for BRAF wild-type (hazard ratio 0.18) (Jones 2017). No colorectal approval covers them, and the encorafenib plus cetuximab label is V600E only.
- Lung cancer: class II and class III alleles (G469A, G466V, K601E, D594G, D594N) outnumber V600E about three to one in lung adenocarcinoma, appearing in roughly 3 to 4% of tumours (cBioPortal). Class III alleles are kinase-impaired and signal as RAS-dependent dimers through CRAF, so a V600-directed inhibitor can activate the pathway rather than block it; class II alleles dimerise independently of RAS. Neither class is covered by the licensed V600E indication.

## Sources

- OJEMDA prescribing information (DailyMed): https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ea3a9631-3a66-6a7c-e053-2995a90ae2ad

## Connected records

- biomarkers: [BRAF fusion or rearrangement](https://onco.cc/biomarkers/braf-fusion/), [BRAF V600E (and V600K)](https://onco.cc/biomarkers/braf-v600e/)
- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Melanoma](https://onco.cc/cancers/melanoma/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Thyroid cancer](https://onco.cc/cancers/thyroid/)
- drugs: [Tovorafenib](https://onco.cc/drugs/tovorafenib/), [Trametinib](https://onco.cc/drugs/trametinib/)
- terms: [BRAF V600E mutation](https://onco.cc/terms/braf-v600-mutation/), [Driver and passenger mutations: the refined somatic mutation theory](https://onco.cc/terms/driver-passenger-model/)
- key papers: [Non-V600 BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancer](https://onco.cc/key-papers/paper-jones-non-v600-braf-colorectal-jco-2017/)
- targets: [BRAF](https://onco.cc/targets/braf/)

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