{"entity":{"id":"ezh2-y646-mutation","kind":"biomarker","name":"EZH2 gain-of-function mutation (Tyr646, originally Tyr641)","aka":["EZH2 Y646","EZH2 Y641","EZH2 mutation","EZH2 Tyr641","EZH2-mutant follicular lymphoma"],"tldr":"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.\n\nThe 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).","asOf":"2026-09-30","links":[{"label":"Morin et al., Nat Genet 2010: somatic EZH2 Tyr641 mutations in follicular and germinal-centre diffuse large B-cell lymphoma","url":"https://doi.org/10.1038/ng.518"},{"label":"Schmitz et al., N Engl J Med 2018: genetics and pathogenesis of diffuse large B-cell lymphoma (574 biopsies; MCD, BN2, N1, EZB)","url":"https://doi.org/10.1056/NEJMoa1801445"}],"tags":["biomarker","lymphoma"],"related":["bcl2-rearrangement"],"cancers":["follicular-lymphoma","dlbcl","non-hodgkin-lymphoma"],"sections":[],"technologies":["cgp"],"targets":["ezh2","bcl2"],"drugs":["tazemetostat"],"companies":[],"institutions":[],"pathways":["epigenetic-reprogramming","germinal-centre-reaction"],"terms":["lymphoma-bio-germinal-centre","lymphoma-bio-lymphgen","flipi","ngs"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"target":"ezh2","measurement":"sequencing-variant","scoringRule":{"text":"Targeted sequencing of the EZH2 SET domain, reported as mutated or wild-type. Sensitivity matters because the mutation is usually heterozygous and may be subclonal; it is normally reported from a lymphoma gene panel on tissue.","quote":"These mutations, which result in the replacement of a single tyrosine in the SET domain of the EZH2 protein (Tyr641), occur in 21.7% of GCB DLBCLs and 7.2% of FLs and are absent from ABC DLBCLs.","source":"https://doi.org/10.1038/ng.518","sourceLabel":"Morin et al., Nature Genetics 2010"},"thresholds":[],"definedBy":{"label":"Morin et al., Nat Genet 2010: somatic EZH2 Tyr641 mutations in follicular and germinal-centre diffuse large B-cell lymphoma","url":"https://doi.org/10.1038/ng.518"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"In relapsed follicular lymphoma this result can open a treatment: tazemetostat, a tablet that blocks the altered enzyme. Response rates are higher in people whose lymphoma carries the mutation than in those whose does not, which is why the test is worth asking about at relapse."},"route":"/biomarkers/ezh2-y646-mutation/","neighbours":{"biomarker":[{"id":"bcl2-rearrangement","kind":"biomarker","name":"BCL2 rearrangement, t(14;18)","route":"/biomarkers/bcl2-rearrangement/"}],"cancer":[{"id":"dlbcl","kind":"cancer","name":"Diffuse large B-cell lymphoma","route":"/cancers/dlbcl/"},{"id":"follicular-lymphoma","kind":"cancer","name":"Follicular lymphoma","route":"/cancers/follicular-lymphoma/"},{"id":"non-hodgkin-lymphoma","kind":"cancer","name":"Non-Hodgkin lymphoma (all types)","route":"/cancers/non-hodgkin-lymphoma/"}],"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"}],"target":[{"id":"bcl2","kind":"target","name":"BCL-2","route":"/targets/bcl2/"},{"id":"ezh2","kind":"target","name":"EZH2","route":"/targets/ezh2/"}],"drug":[{"id":"tazemetostat","kind":"drug","name":"Tazemetostat","route":"/drugs/tazemetostat/"}],"pathway":[{"id":"epigenetic-reprogramming","kind":"pathway","name":"Epigenetic reprogramming","route":"/pathways/epigenetic-reprogramming/"},{"id":"germinal-centre-reaction","kind":"pathway","name":"The germinal centre reaction","route":"/pathways/germinal-centre-reaction/"}],"term":[{"id":"flipi","kind":"term","name":"FLIPI, FLIPI2 and POD24 (follicular lymphoma risk)","route":"/terms/flipi/"},{"id":"lymphoma-bio-lymphgen","kind":"term","name":"LymphGen and the genetic clusters of large B-cell lymphoma","route":"/terms/lymphoma-bio-lymphgen/"},{"id":"ngs","kind":"term","name":"Next-generation sequencing (NGS)","route":"/terms/ngs/"},{"id":"lymphoma-bio-germinal-centre","kind":"term","name":"The germinal centre: why lymphoma starts where antibodies are made","route":"/terms/lymphoma-bio-germinal-centre/"}]}}