EZH2 Y646F

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Molecular profile	Therapy	Type	Level	Direction · significance	Rating (1–5)	Status	Evidence	Source
B-Cell Malignant Neoplasm4
EZH2 Y646F	(oncogenic)	Oncogenic	D	Supports Oncogenicity	4	accepted	EID10394 Ezh2 Y641F (EZH2 Y641F) was conditionally expressed in mouse B-cells and caused high-penetrance lymphoma that was further accelerated by Bcl2 overexpression or p53 loss (but not c-Myc overexpression).… (full text at CIViC) PMID 27135738 · Souroullas et al., 2016 · Open in CIViC	civic
EZH2 Y646F	(oncogenic)	Oncogenic	D	Supports Oncogenicity	4	submitted	EID12407 This study provides preclinical evidence that EZH2 Y641N and Y641F mutations function as oncogenic drivers in B-cell lymphomas. In BCL1 lymphoma cells, expression of either mutant led to increased H3K… (full text at CIViC) PMID 23680150 · Béguelin et al., 2013 · Open in CIViC	civic

Molecular profile

Therapy

Type

Level

Direction · significance

Rating (1–5)

Status

Evidence

Source

B-Cell Malignant Neoplasm4

EZH2 Y646F

(oncogenic)

Oncogenic

Supports Oncogenicity

accepted

EID10394

Ezh2 Y641F (EZH2 Y641F) was conditionally expressed in mouse B-cells and caused high-penetrance lymphoma that was further accelerated by Bcl2 overexpression or p53 loss (but not c-Myc overexpression).… (full text at CIViC)

PMID 27135738 · Souroullas et al., 2016 · Open in CIViC

civic

EZH2 Y646F

(oncogenic)

Oncogenic

Supports Oncogenicity

submitted

EID12407

This study provides preclinical evidence that EZH2 Y641N and Y641F mutations function as oncogenic drivers in B-cell lymphomas. In BCL1 lymphoma cells, expression of either mutant led to increased H3K… (full text at CIViC)

PMID 23680150 · Béguelin et al., 2013 · Open in CIViC

civic

B-Cell Non-Hodgkin Lymphoma1
EZH2 Y646S OR EZH2 Y646F OR EZH2 Y646H OR EZH2 Y646C OR EZH2 Y646N OR EZH2 A692V OR EZH2 A682G	Tazemetostat	Predictive	A	Supports Sensitivity Response	2	accepted	EID11220 In a multicentre, open-label, phase 1 trial, tazemetostat was evaluated in 64 adult patients (≥18 years) with relapsed or refractory B-cell non-Hodgkin lymphoma (n=21) or advanced solid tumours (n=43)… (full text at CIViC) PMID 29650362 · Italiano et al., 2018 · Open in CIViC	civic

B-Cell Non-Hodgkin Lymphoma1

EZH2 Y646S OR EZH2 Y646F OR EZH2 Y646H OR EZH2 Y646C OR EZH2 Y646N OR EZH2 A692V OR EZH2 A682G

Tazemetostat

Predictive

Supports Sensitivity Response

accepted

EID11220

In a multicentre, open-label, phase 1 trial, tazemetostat was evaluated in 64 adult patients (≥18 years) with relapsed or refractory B-cell non-Hodgkin lymphoma (n=21) or advanced solid tumours (n=43)… (full text at CIViC)

PMID 29650362 · Italiano et al., 2018 · Open in CIViC

civic

Cutaneous Melanoma1
EZH2 Y646F	(prognostic)	Prognostic	D	Supports Poor Outcome	5	submitted	EID8036 Conditional expression of mouse equivalent mutation Ezh2(Y641F) in melanocytes caused high penetrance melanoma PMID 27135738 · Souroullas et al., 2016 · Open in CIViC	civic

Cutaneous Melanoma1

EZH2 Y646F

(prognostic)

Prognostic

Supports Poor Outcome

submitted

EID8036

Conditional expression of mouse equivalent mutation Ezh2(Y641F) in melanocytes caused high penetrance melanoma

PMID 27135738 · Souroullas et al., 2016 · Open in CIViC

civic

Diffuse Large B-Cell Lymphoma4
EZH2 Y646F	(oncogenic)	Oncogenic	D	Supports Oncogenicity	3	submitted	EID11012 A selective EZH2 inhibitor (EI1) and siRNA were used to inhibit EZH2 Y641F mutation in DLBCL mutated cell line (WSU-DLCL2). Two independent siRNAs knocked down EZH2 mRNA by almost 80% and inhibited c… (full text at CIViC) PMID 23236167 · Qi et al., 2012 · Open in CIViC	civic
EZH2 Y646F	EPZ011989	Predictive	D	Supports Sensitivity Response	3	submitted	EID11025 In this preclinical study, authors aimed to study EZH2 inhibition effect on PRAME in DLBCL. IμBcl6 EZH2-Y646F Cγ1-Cre mice were used for in vivo experiment using a vehicle or EZH2 inhibitor, EPZ011989… (full text at CIViC) PMID 35380993 · Takata et al., 2022 · Open in CIViC	civic
EZH2 Y646F	GSK126	Predictive	D	Supports Sensitivity Response	3	submitted	EID11106 EZH2 inhibitor, GSK126, showed high potency against DLBCL cell lines, WSU-DLCL2 and SU-DHL-10, harboring the Y646F variant. Cell proliferation inhibition was measured after six days at growth IC50= 13… (full text at CIViC) PMID 23051747 · McCabe et al., 2012 · Open in CIViC	civic
EZH2 Y646S OR EZH2 Y646F OR EZH2 Y646H OR EZH2 Y646C OR EZH2 Y646N OR EZH2 A692V OR EZH2 A682G	Tazemetostat	Predictive	B	Supports Sensitivity Response	3	accepted	EID11110 This phase II study evaluated the efficacy and safety of the EZH2 inhibitor tazemetostat in Japanese adults with relapsed or refractory B-cell non-Hodgkin lymphoma harboring EZH2-activating mutations … (full text at CIViC) PMID 34159682 · Izutsu et al., 2021 · Open in CIViC	civic

Diffuse Large B-Cell Lymphoma4

EZH2 Y646F

(oncogenic)

Oncogenic

Supports Oncogenicity

submitted

EID11012

A selective EZH2 inhibitor (EI1) and siRNA were used to inhibit EZH2 Y641F mutation in DLBCL mutated cell line (WSU-DLCL2). Two independent siRNAs knocked down EZH2 mRNA by almost 80% and inhibited c… (full text at CIViC)

PMID 23236167 · Qi et al., 2012 · Open in CIViC

civic

EZH2 Y646F

EPZ011989

Predictive

Supports Sensitivity Response

submitted

EID11025

In this preclinical study, authors aimed to study EZH2 inhibition effect on PRAME in DLBCL. IμBcl6 EZH2-Y646F Cγ1-Cre mice were used for in vivo experiment using a vehicle or EZH2 inhibitor, EPZ011989… (full text at CIViC)

PMID 35380993 · Takata et al., 2022 · Open in CIViC

civic

EZH2 Y646F

GSK126

Predictive

Supports Sensitivity Response

submitted

EID11106

EZH2 inhibitor, GSK126, showed high potency against DLBCL cell lines, WSU-DLCL2 and SU-DHL-10, harboring the Y646F variant. Cell proliferation inhibition was measured after six days at growth IC50= 13… (full text at CIViC)

PMID 23051747 · McCabe et al., 2012 · Open in CIViC

civic

EZH2 Y646S OR EZH2 Y646F OR EZH2 Y646H OR EZH2 Y646C OR EZH2 Y646N OR EZH2 A692V OR EZH2 A682G

Tazemetostat

Predictive

Supports Sensitivity Response

accepted

EID11110

This phase II study evaluated the efficacy and safety of the EZH2 inhibitor tazemetostat in Japanese adults with relapsed or refractory B-cell non-Hodgkin lymphoma harboring EZH2-activating mutations … (full text at CIViC)

PMID 34159682 · Izutsu et al., 2021 · Open in CIViC

civic

Follicular Lymphoma2
EZH2 Y646S OR EZH2 Y646F OR EZH2 Y646H OR EZH2 Y646C OR EZH2 Y646N OR EZH2 A692V OR EZH2 A682G	(oncogenic)	Oncogenic	B	Supports Oncogenicity	4	accepted	EID11111 In this large cohort study, 366 patients with follicular lymphoma (FL) were recruited to investigate the incidence and distribution of EZH2 mutations. NGS and Sanger detected EZH2 positive mutations i… (full text at CIViC) PMID 24052547 · Bödör et al., 2013 · Open in CIViC	civic
EZH2 Y646S OR EZH2 Y646F OR EZH2 Y646H OR EZH2 Y646C OR EZH2 Y646N OR EZH2 A692V OR EZH2 A682G	Tazemetostat	Predictive	B	Supports Sensitivity Response	4	accepted	EID11109 In this study, Koji Izutsu et al. conducted a multicenter, open-label phase II clinical trial to evaluate the efficacy and safety of the EZH2 inhibitor tazemetostat in Japanese patients with relapsed … (full text at CIViC) PMID 34159682 · Izutsu et al., 2021 · Open in CIViC	civic

Follicular Lymphoma2

EZH2 Y646S OR EZH2 Y646F OR EZH2 Y646H OR EZH2 Y646C OR EZH2 Y646N OR EZH2 A692V OR EZH2 A682G

(oncogenic)

Oncogenic

Supports Oncogenicity

accepted

EID11111

In this large cohort study, 366 patients with follicular lymphoma (FL) were recruited to investigate the incidence and distribution of EZH2 mutations. NGS and Sanger detected EZH2 positive mutations i… (full text at CIViC)

PMID 24052547 · Bödör et al., 2013 · Open in CIViC

civic

EZH2 Y646S OR EZH2 Y646F OR EZH2 Y646H OR EZH2 Y646C OR EZH2 Y646N OR EZH2 A692V OR EZH2 A682G

Tazemetostat

Predictive

Supports Sensitivity Response

accepted

EID11109

In this study, Koji Izutsu et al. conducted a multicenter, open-label phase II clinical trial to evaluate the efficacy and safety of the EZH2 inhibitor tazemetostat in Japanese patients with relapsed … (full text at CIViC)

PMID 34159682 · Izutsu et al., 2021 · Open in CIViC

civic

Melanoma1
BRAF V600E AND EZH2 Y646F	JQEZ5	Predictive	D	Supports Sensitivity Response	4	accepted	EID6952 Experiment with immunodeficient mice transplanted with melanoma cell lines indicates EZH2 inhibitor JQEZ5 might be effective in combination with a B-RAF inhibitor in RAF-mutant melanoma. PMID 27135738 · Souroullas et al., 2016 · Open in CIViC	civic

Melanoma1

BRAF V600E AND EZH2 Y646F

JQEZ5

Predictive

Supports Sensitivity Response

accepted

EID6952

Experiment with immunodeficient mice transplanted with melanoma cell lines indicates EZH2 inhibitor JQEZ5 might be effective in combination with a B-RAF inhibitor in RAF-mutant melanoma.

PMID 27135738 · Souroullas et al., 2016 · Open in CIViC

civic

Non-Hodgkin Lymphoma2
EZH2 Y646F	Tazemetostat	Predictive	D	Supports Sensitivity Response	4	submitted	EID11000 In this preclinical study, authors aimed to study the effect of combining glucocorticoid receptor agonists with the EZP-6438 inhibitor in NHL. WSU-DLCL2 lymphoma cells harboring the Y646F mutation we… (full text at CIViC) PMID 25493630 · Knutson et al., 2014 · Open in CIViC	civic
EZH2 Y646F	Tazemetostat	Predictive	D	Supports Sensitivity Response	3	submitted	EID11048 To study EZH2 blocking outcome on TADs, authors used EPZ6438 in NHL cell line, OCI-Ly19-EZH2 carrying the Y646F mutation. EZH2 inhibition efficiently depleted H3K27me3 in lymphoma cells and exhibited … (full text at CIViC) PMID 30692681 · Donaldson-Collier et al., 2019 · Open in CIViC	civic

Non-Hodgkin Lymphoma2

EZH2 Y646F

Tazemetostat

Predictive

Supports Sensitivity Response

submitted

EID11000

In this preclinical study, authors aimed to study the effect of combining glucocorticoid receptor agonists with the EZP-6438 inhibitor in NHL. WSU-DLCL2 lymphoma cells harboring the Y646F mutation we… (full text at CIViC)

PMID 25493630 · Knutson et al., 2014 · Open in CIViC

civic

EZH2 Y646F

Tazemetostat

Predictive

Supports Sensitivity Response

submitted

EID11048

To study EZH2 blocking outcome on TADs, authors used EPZ6438 in NHL cell line, OCI-Ly19-EZH2 carrying the Y646F mutation. EZH2 inhibition efficiently depleted H3K27me3 in lymphoma cells and exhibited … (full text at CIViC)

PMID 30692681 · Donaldson-Collier et al., 2019 · Open in CIViC

civic

Unmapped disease4unmapped disease
EZH2 Y646F	(functional)	Functional	D	Supports Gain Of Function	3	rejected	EID9516 H3K27me3 level was higher in EZH2 (Y641F) bearing GCB-derived lymphoma cell lines and tumors than in wild-type cells. Expression of Y641F mutation in HEK293T cells with wild-type EZH2 led to an increa… (full text at CIViC) PMID 21190999 · Yap et al., 2011 · Open in CIViC	civic
EZH2 Y646F	(functional)	Functional	D	Supports Gain Of Function	3	accepted	EID9517 H3K27me3 (histone H3 Lys-27–specific trimethylation) level was higher in EZH2 (Y641F) bearing germinal center B-cell type DLBCL derived lymphoma cell lines and tumors than in wild-type cells. There wa… (full text at CIViC) PMID 21190999 · Yap et al., 2011 · Open in CIViC	civic
EZH2 Y646F	(functional)	Functional	D	Supports Loss Of Function	3	accepted	EID9519 A 3H methyl incorporation assay tested the function of EZH2 Y641F containing PRC2 complexes in vitro. It showed that Y641F/N PRC2 complexes had significantly decreased enzyme activity on unmethylated … (full text at CIViC) PMID 21190999 · Yap et al., 2011 · Open in CIViC	civic
EZH2 Y646F	(functional)	Functional	D	Supports Gain Of Function	2	submitted	EID11010 DLBCL cell line carrying the EZH2 Y641F mutation (WSU-DLCL2 ) was used to study the effect of a selective EZH2 inhibitor (EI1) on these cells. Immunoblot assay showed an increase in baseline H3K27me3 … (full text at CIViC) PMID 23236167 · Qi et al., 2012 · Open in CIViC	civic

Unmapped disease4unmapped disease

EZH2 Y646F

(functional)

Functional

Supports Gain Of Function

rejected

EID9516

H3K27me3 level was higher in EZH2 (Y641F) bearing GCB-derived lymphoma cell lines and tumors than in wild-type cells. Expression of Y641F mutation in HEK293T cells with wild-type EZH2 led to an increa… (full text at CIViC)

PMID 21190999 · Yap et al., 2011 · Open in CIViC

civic

EZH2 Y646F

(functional)

Functional

Supports Gain Of Function

accepted

EID9517

H3K27me3 (histone H3 Lys-27–specific trimethylation) level was higher in EZH2 (Y641F) bearing germinal center B-cell type DLBCL derived lymphoma cell lines and tumors than in wild-type cells. There wa… (full text at CIViC)

PMID 21190999 · Yap et al., 2011 · Open in CIViC

civic

EZH2 Y646F

(functional)

Functional

Supports Loss Of Function

accepted

EID9519

A 3H methyl incorporation assay tested the function of EZH2 Y641F containing PRC2 complexes in vitro. It showed that Y641F/N PRC2 complexes had significantly decreased enzyme activity on unmethylated … (full text at CIViC)

PMID 21190999 · Yap et al., 2011 · Open in CIViC

civic

EZH2 Y646F

(functional)

Functional

Supports Gain Of Function

submitted

EID11010

DLBCL cell line carrying the EZH2 Y641F mutation (WSU-DLCL2 ) was used to study the effect of a selective EZH2 inhibitor (EI1) on these cells. Immunoblot assay showed an increase in baseline H3K27me3 … (full text at CIViC)

PMID 23236167 · Qi et al., 2012 · Open in CIViC

civic

Evidence by cancer (19 items)

Clinical significance (0)