# EZH2 gain-of-function mutation (Tyr646, originally Tyr641)

Source: https://onco.cc/biomarkers/ezh2-y646-mutation/  
OnCo record `ezh2-y646-mutation` (Biomarker). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

A change in an enzyme that puts a chemical silencing mark on DNA. The altered enzyme adds too much of the mark, which keeps a lymphoma cell locked in the state it should have grown out of. It is the one lymphoma mutation that currently selects a tablet.

## Summary

EZH2 is the catalytic subunit of polycomb repressive complex 2 and writes the H3K27 trimethyl mark. In lymphoma the mutations replace a single tyrosine in the SET domain, Tyr641 in the original numbering and Tyr646 in current usage. They are not simple activating mutations: the altered enzyme is better at converting the di-methyl mark to the tri-methyl mark and worse at making the first methylation, so a cell with one mutant and one wild-type allele accumulates H3K27me3 and holds the germinal-centre programme shut. This is the opposite direction to the loss-of-function EZH2 mutations found in myeloid disease, which is a standing source of confusion in the literature.

The substitutions occur in 21.7% of germinal-centre diffuse large B-cell lymphomas and 7.2% of follicular lymphomas, and are absent from the activated B-cell-like subtype (Morin 2010). EZH2 mutation with BCL2 translocation defines the EZB genetic subtype (Schmitz 2018).

## Fields

- Kind: Biomarker
- Last checked: 2026-09-30
- Also known as: EZH2 Y646; EZH2 Y641; EZH2 mutation; EZH2 Tyr641; EZH2-mutant follicular lymphoma
- Tags: biomarker; lymphoma

## Sources

- Morin et al., Nat Genet 2010: somatic EZH2 Tyr641 mutations in follicular and germinal-centre diffuse large B-cell lymphoma: https://doi.org/10.1038/ng.518
- Schmitz et al., N Engl J Med 2018: genetics and pathogenesis of diffuse large B-cell lymphoma (574 biopsies; MCD, BN2, N1, EZB): https://doi.org/10.1056/NEJMoa1801445

## Connected records

- biomarkers: [BCL2 rearrangement, t(14;18)](https://onco.cc/biomarkers/bcl2-rearrangement/)
- cancers: [Diffuse large B-cell lymphoma](https://onco.cc/cancers/dlbcl/), [Follicular lymphoma](https://onco.cc/cancers/follicular-lymphoma/), [Non-Hodgkin lymphoma (all types)](https://onco.cc/cancers/non-hodgkin-lymphoma/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/)
- targets: [BCL-2](https://onco.cc/targets/bcl2/), [EZH2](https://onco.cc/targets/ezh2/)
- drugs: [Tazemetostat](https://onco.cc/drugs/tazemetostat/)
- pathways: [Epigenetic reprogramming](https://onco.cc/pathways/epigenetic-reprogramming/), [The germinal centre reaction](https://onco.cc/pathways/germinal-centre-reaction/)
- terms: [FLIPI, FLIPI2 and POD24 (follicular lymphoma risk)](https://onco.cc/terms/flipi/), [LymphGen and the genetic clusters of large B-cell lymphoma](https://onco.cc/terms/lymphoma-bio-lymphgen/), [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/), [The germinal centre: why lymphoma starts where antibodies are made](https://onco.cc/terms/lymphoma-bio-germinal-centre/)

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