[Paper-level Aggregated] PMCID: PMC4899144

Evidence Type(s): Functional

Summary: Mutation: Y641F | Summary: The Y641F mutation alters molecular function by affecting global levels of H3K27me3, enzymatic activity, and gene expression regulation in B-cells and melanoma cells. It is associated with a gain-of-function effect, increased apoptotic resistance, and a global redistribution of H3K27me3 marks across the genome. The mutation also alters the expression of numerous transcripts and affects the distribution of H3K27me3 at promoter regions.

Evidence Type: Functional Mutation: Y646F | Summary: The Y646F mutation is described as equivalent to the Y641F mutation, suggesting it alters molecular function, although specific functional data is limited. It affects the molecular function of Ezh2 and exhibits in vitro activity against the JQEZ5 inhibitor, indicating a correlation with treatment response.

Gene→Variant (gene-first): EZH2(2146):Y641F EZH2(2146):Y646F

Genes: EZH2(2146)

Variants: Y641F Y646F

[Paper-level Aggregated] PMCID: PMC4899144

Evidence Type(s): Oncogenic

Summary: Mutation: Y641F | Summary: The Y641F mutation in EZH2 contributes to tumor development in B-cell lymphomas and melanoma, as it induces highly penetrant B-cell lymphoma in mice, is associated with splenomegaly and lymphadenopathy, and affects gene expression regulated by PRC2. It is equivalent to a common EZH2 missense mutation found in human cancers, indicating its role in malignancy and tumor progression. The mutation alters the epigenetic landscape by affecting H3K27me3 distribution and is implicated in tumor initiation and maintenance.

Evidence Type: Oncogenic Mutation: Y646F | Summary: The Y646F mutation in EZH2 is associated with tumor development and progression in melanoma, and is noted as one of the most common EZH2 missense mutations in human cancers. It is suggested to alter molecular function, although specific functional data is limited.

Evidence Type: Oncogenic Mutation: B-RAFV600E | Summary: The B-RAFV600E mutation is implicated in the majority of human melanomas, contributing to tumor development and progression through RAF/MEK/ERK activation. It is associated with oncogene-induced senescence and cooperates with the Ezh2Y641F mutation to accelerate tumorigenesis in melanoma.

Gene→Variant (gene-first): EZH2(2146):Y641F EZH2(2146):Y646F BRAF(673):B-RAFV600E

Genes: EZH2(2146) BRAF(673)

Variants: Y641F Y646F B-RAFV600E

[Paper-level Aggregated] PMCID: PMC4899144

Evidence Type(s): Prognostic

Summary: Mutation: Y641F | Summary: The presence of the Ezh2Y641F mutation correlates with a median survival of one year in tumor-bearing mice, indicating its association with disease outcome.

Gene→Variant (gene-first): EZH2(2146):Y641F

Genes: EZH2(2146)

Variants: Y641F

[Paper-level Aggregated] PMCID: PMC4899144

Evidence Type(s): Predictive

Summary: Mutation: Y641F | Summary: The Y641F mutation in Ezh2 is associated with increased sensitivity to the EZH2 inhibitor JQEZ5, indicating a correlation with treatment response and predictive value for treatment efficacy in B-cell lymphoma and melanoma models.

Evidence Type: Predictive Mutation: Y646F | Summary: The Y646F mutation exhibits in vitro activity against the JQEZ5 inhibitor, suggesting a correlation with treatment response.

Gene→Variant (gene-first): EZH2(2146):Y641F EZH2(2146):Y646F

Genes: EZH2(2146)

Variants: Y641F Y646F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 23

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: Y641F | Summary: The Ezh2Y641F mutation alters the molecular function of the enzyme, leading to a global redistribution of H3K27me3 marks across the genome in melanoma cell lines. Evidence Type: Oncogenic | Mutation: Y641F | Summary: The Ezh2Y641F mutation contributes to tumor development by affecting the epigenetic landscape, as indicated by changes in H3K27me3 distribution in melanoma cell lines.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 22

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: Y641F | Summary: The Ezh2Y641F mutation alters the H3K27me3 signal around the transcription start site and gene body, indicating a change in molecular function related to gene expression regulation. Evidence Type: Oncogenic | Mutation: Y641F | Summary: The Ezh2Y641F mutation is associated with changes in gene expression in B-cells and melanoma cell lines, suggesting its role in tumor development or progression.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 21

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: Y641F | Summary: The Ezh2Y641F mutation alters the distribution of H3K27me3 at promoter regions and affects gene expression, indicating a change in molecular function related to transcription regulation. Evidence Type: Oncogenic | Mutation: Y641F | Summary: The Ezh2Y641F mutation contributes to tumor development by affecting the expression of genes regulated by PRC2, suggesting its role in cancer progression.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: Y641F | Summary: The Ezh2Y641F mutation alters the expression of numerous transcripts in both B-cells and melanoma cells, indicating a change in molecular function associated with this variant. Evidence Type: Oncogenic | Mutation: Y641F | Summary: The Ezh2Y641F mutation is implicated in tumor development as it is expressed in melanoma cell lines derived from tumors, suggesting a role in cancer progression.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 13

Evidence Type(s): Predictive, Oncogenic

Summary: Evidence Type: Predictive | Mutation: Y641F | Summary: The Y641F mutation in EZH2 is associated with response to the EZH2 inhibitor JQEZ5, indicating its predictive value for treatment efficacy in B-cell lymphoma and melanoma models. Evidence Type: Oncogenic | Mutation: Y641F | Summary: The Y641F mutation in EZH2 contributes to tumor development in B-cell lymphoma, as evidenced by its presence in autochthonous tumor models.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 12

Evidence Type(s): Predictive, Oncogenic, Functional

Summary: Evidence Type: Predictive | Mutation: Y641F | Summary: The Y641F mutation in Ezh2 is associated with increased sensitivity to the EZH2 inhibitor JQEZ5, indicating a correlation with treatment response. Evidence Type: Oncogenic | Mutation: Y641F | Summary: The Y641F mutation in Ezh2 is implicated in tumor initiation and maintenance, contributing to tumor development in melanoma. Evidence Type: Functional | Mutation: Y641F | Summary: The Y641F mutation alters the enzymatic activity of Ezh2, as evidenced by the differential response to EZH2 inhibitors in cell lines. Evidence Type: Predictive | Mutation: Y646F | Summary: The Y646F mutation exhibits in vitro activity against the JQEZ5 inhibitor, suggesting a correlation with treatment response. Evidence Type: Oncogenic | Mutation: Y646F | Summary: The Y646F mutation in Ezh2 is involved in tumor development and progression in melanoma. Evidence Type: Functional | Mutation: Y646F | Summary: The Y646F mutation affects the molecular function of Ezh2, as indicated by its response to pharmacological inhibitors.

Gene→Variant (gene-first): 2146:Y641F 2146:Y646F

Genes: 2146

Variants: Y641F Y646F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 10

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: B-RAFV600E | Summary: The B-RAFV600E mutation is implicated in oncogene-induced senescence and contributes to tumor development as indicated by its role in the experimental setup involving primary human melanocytes. Evidence Type: Oncogenic | Mutation: Y641F | Summary: The Y641F mutation in EZH2 is suggested to have oncogenic effects, as the experiments indicate that RAS-PI3K activation can attenuate its oncogenic effects in the context of melanoma formation.

Gene→Variant (gene-first): 673:B-RAFV600E 2146:Y641F

Genes: 673 2146

Variants: B-RAFV600E Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: B-RafV600E | Summary: B-RafV600E is implicated in promoting melanoma through RAF/MEK/ERK activation, indicating its role in tumor development. Evidence Type: Oncogenic | Mutation: Ezh2Y641F | Summary: Ezh2Y641F is suggested to have oncogenic effects in melanoma formation, although its impact is rendered irrelevant in the presence of mutant RAS signaling.

Gene→Variant (gene-first): 673:B-RafV600E 2146:Y641F

Genes: 673 2146

Variants: B-RafV600E Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 8

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: B-RAFV600E | Summary: The B-RAFV600E mutation is implicated in the majority of human melanomas and contributes to tumor development and progression. Evidence Type: Oncogenic | Mutation: Ezh2Y641F | Summary: The Ezh2Y641F mutation cooperates with the B-RAFV600E mutation to accelerate tumorigenesis in melanoma, indicating its role in cancer development. Evidence Type: Oncogenic | Mutation: B-RafV600E | Summary: The B-RafV600E mutation is associated with melanoma formation and progression, demonstrating its oncogenic potential.

Gene→Variant (gene-first): 673:B-RAFV600E 673:B-RafV600E 2146:Y641F

Genes: 673 2146

Variants: B-RAFV600E B-RafV600E Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: Y641F | Summary: The Y641F mutation in EZH2 exhibits altered methylase activity, demonstrating a change in molecular function compared to wild-type EZH2. Evidence Type: Oncogenic | Mutation: Y641F | Summary: The presence of the Y641F mutation contributes to tumorigenesis, as evidenced by the development of splenomegaly and lymphadenopathy in mice harboring this mutation. Evidence Type: Functional | Mutation: Y646 | Summary: The passage suggests that mutations at position Y646 may also affect molecular function, although specific details are not provided.

Gene→Variant (gene-first): 2146:Y641F 2146:Y646 2146:tyrosine to phenylalanine

Genes: 2146

Variants: Y641F Y646 tyrosine to phenylalanine

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: Y641F | Summary: The Ezh2Y641F mutation contributes to tumor development and progression in B-cell lymphomas, as indicated by its role in accelerating lymphoma formation when combined with other genetic alterations. Evidence Type: Functional | Mutation: Y641F | Summary: The Ezh2Y641F variant alters molecular function by affecting the global levels of H3K27me3, which is associated with apoptotic resistance and B-cell transformation.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic, Prognostic

Summary: Evidence Type: Oncogenic | Mutation: Y641F | Summary: The Ezh2Y641F mutation contributes to tumor development, as it induces highly penetrant B-cell lymphoma in mice, demonstrating its role in malignancy. Evidence Type: Prognostic | Mutation: Y641F | Summary: The presence of the Ezh2Y641F mutation correlates with a median survival of one year in tumor-bearing mice, indicating its association with disease outcome.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: Y641F | Summary: The Y641F mutation alters molecular function, as it is associated with a gain-of-function effect, leading to increased H3K27me3 levels in B-cells. Evidence Type: Oncogenic | Mutation: Y641F | Summary: The Y641F mutation is equivalent to a common EZH2 missense mutation found in human cancers, indicating its contribution to tumor development. Evidence Type: Functional | Mutation: Y646F | Summary: The Y646F mutation is described as equivalent to the Y641F mutation, suggesting it also alters molecular function, although specific functional data for Y646F is not detailed in the passage. Evidence Type: Oncogenic | Mutation: Y646F | Summary: The Y646F mutation is noted as one of the most common EZH2 missense mutations in human cancers, indicating its role in tumor development.

Gene→Variant (gene-first): 2146:Y641F 2146:Y646F

Genes: 2146

Variants: Y641F Y646F

[Paragraph-level] PMCID: PMC4899144 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: Y641F | Summary: The Y641F mutation in EZH2 contributes to tumor development in mouse B-cells, leading to high-penetrance lymphoma. Evidence Type: Oncogenic | Mutation: Y646F | Summary: The Y646F mutation in EZH2 is associated with tumor progression in melanoma, as demonstrated in a mouse model.

Gene→Variant (gene-first): 2146:Y641F 2146:Y646F

Genes: 2146

Variants: Y641F Y646F

[Paper-level Aggregated] PMCID: PMC4899144

Evidence Type(s): Oncogenic, Functional, Predictive, Prognostic

Justification: Oncogenic: The expression of the Ezh2Y641F mutation in mouse B-cells and melanocytes led to the development of high-penetrance lymphoma and melanoma, indicating its role in promoting cancer. Functional: The study demonstrated that Ezh2Y641F exhibits altered enzymatic activity, with decreased mono-methylase activity but increased di- and tri-methylase activity, suggesting a functional change associated with the mutation. Predictive: The presence of the Ezh2Y641F mutation was shown to cooperate with B-RAFV600E in accelerating melanoma formation, indicating its potential to predict tumorigenesis in the context of specific genetic alterations. Prognostic: The study reported that mice expressing Ezh2Y641F had a median survival of one year, suggesting that the mutation may have implications for disease progression and patient outcomes.

Gene→Variant (gene-first): BRAF(673):B-RAFV600E BRAF(673):B-RafV600E EZH2(2146):Y641F EZH2(2146):Y646 EZH2(2146):tyrosine to phenylalanine EZH2(2146):Y646F

Genes: BRAF(673) EZH2(2146)

Variants: B-RAFV600E B-RafV600E Y641F Y646 tyrosine to phenylalanine Y646F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 23

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the Ezh2Y641F mutation alters the molecular function of the enzyme, specifically its effect on H3K27me3 distribution, indicating a change in biochemical activity. Oncogenic: The context of the study involves analyzing the Ezh2Y641F mutation in melanoma cell lines, suggesting that this somatic variant contributes to tumor development or progression.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 22

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the Ezh2Y641F variant affects the H3K27me3 signal around the transcription start site and gene body, indicating an alteration in molecular function related to gene expression regulation. Oncogenic: The variant Ezh2Y641F is associated with changes in gene expression in cancer cell lines, suggesting its role in tumor development or progression.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 21

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the Ezh2Y641F variant alters the distribution of H3K27me3, indicating a change in molecular function related to gene expression and chromatin modification.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the Ezh2Y641F variant alters the expression of numerous transcripts in B-cells and melanoma cells, indicating a change in molecular function related to gene expression. Oncogenic: The variant Ezh2Y641F is associated with melanoma cell lines derived from tumors, suggesting its role in tumor development or progression.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 13

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the anti-tumor efficacy of EZH2 inhibitors and their effects on tumor growth inhibition in Ezh2Y641F/+ tumors, indicating a correlation with treatment response. Oncogenic: The variant Ezh2Y641F is implicated in tumor development, as it is studied in the context of autochthonous tumors in mice, suggesting its role in contributing to tumor progression.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 12

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the response of melanoma cell lines with the Y641F variant to various EZH2 inhibitors, indicating a correlation between the variant and sensitivity to treatment. Functional: The passage describes how the Y641F variant affects the potency of the JQEZ5 inhibitor, demonstrating that the variant alters the molecular function of EZH2 in the context of drug response.

Gene→Variant (gene-first): 2146:Y641F 2146:Y646F

Genes: 2146

Variants: Y641F Y646F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 10

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the oncogenic effects of the B-RAFV600E and Ezh2Y641F mutations in the context of melanoma formation, indicating that these variants contribute to tumor development or progression. Functional: The passage describes how the presence of the Y641F mutation does not alter the expression of certain genes, suggesting that it may affect molecular or biochemical functions related to oncogenic pathways.

Gene→Variant (gene-first): 673:B-RAFV600E 2146:Y641F

Genes: 673 2146

Variants: B-RAFV600E Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the role of B-RafV600E and Ezh2Y641F in promoting melanoma, indicating that these variants contribute to tumor development or progression. Functional: The mention of B-Raf as a downstream effector of N-RAS signaling suggests that the variant B-RafV600E alters molecular function in the context of signaling pathways involved in melanoma.

Gene→Variant (gene-first): 673:B-RafV600E 2146:Y641F

Genes: 673 2146

Variants: B-RafV600E Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 8

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage describes how the Ezh2Y641F mutation cooperates with the B-RAFV600E mutation to accelerate tumorigenesis in melanoma, indicating that it contributes to tumor development. Functional: The passage implies that the Ezh2Y641F mutation alters the tumorigenic process in conjunction with B-RAFV600E, suggesting a change in molecular function related to tumor maintenance and formation.

Gene→Variant (gene-first): 673:B-RAFV600E 673:B-RafV600E 2146:Y641F

Genes: 673 2146

Variants: B-RAFV600E B-RafV600E Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the EZH2Y641F variant exhibits altered methylase activity, indicating that the variant affects molecular function. Oncogenic: The evidence suggests that the EZH2Y641F mutation contributes to tumor development, as demonstrated by the tumorigenesis observed in mice harboring this mutation.

Gene→Variant (gene-first): 2146:Y641F 2146:Y646 2146:tyrosine to phenylalanine

Genes: 2146

Variants: Y641F Y646 tyrosine to phenylalanine

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how the Ezh2Y641F variant contributes to tumor formation in B-cell lymphomas, indicating its role in tumor development and progression. Functional: The variant is associated with altered molecular function, specifically in the context of its cooperation with other genetic alterations to influence B-cell transformation and apoptotic resistance.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic, Prognostic

Justification: Oncogenic: The passage describes how the Ezh2Y641F variant contributes to the development of B-cell lymphoma in mice, indicating its role in tumor progression. Prognostic: The median survival of one year for mice with the Ezh2Y641F variant suggests a correlation with disease outcome, specifically survival, independent of therapy.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the Y641F mutation alters the expression of Ezh2 transcripts and leads to a gain-of-function effect, evidenced by the increase in H3K27me3 levels in B-cells, indicating a change in molecular function. Oncogenic: The Y641F mutation is described as equivalent to a common EZH2 missense mutation found in human cancers, suggesting its role in tumor development or progression.

Gene→Variant (gene-first): 2146:Y641F 2146:Y646F

Genes: 2146

Variants: Y641F Y646F

[Paragraph-level] PMCID: PMC4899144 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage describes how the somatic mutations Y641F and Y646F in the EZH2 gene contribute to tumor development, specifically leading to high-penetrance lymphoma and melanoma in a mouse model. Functional: The variant Ezh2Y641F is shown to alter molecular function by increasing global H3K27 trimethylation and causing a redistribution of this mark, which affects transcription at various loci.

Gene→Variant (gene-first): 2146:Y641F 2146:Y646F

Genes: 2146

Variants: Y641F Y646F

[Paragraph-level] PMCID: PMC4899144 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage describes how the somatic mutations Y641F and Y646F in the EZH2 gene contribute to tumor development, specifically leading to high-penetrance lymphoma and melanoma in a mouse model. Functional: The variant Ezh2Y641F is shown to alter molecular function by increasing global H3K27 trimethylation and causing a redistribution of this mark, which affects transcription at various loci.

Gene→Variant (gene-first): 2146:Y641F 2146:Y646F

Genes: 2146

Variants: Y641F Y646F