EZH2 V662A Discovery
Novel unreported variant, SET domain loss-of-function, PRC2 sixth axis
PubMed Hits Novel
0
0 results for 'EZH2 V662A' or 'EZH2 V662'
EVE Score Uncertain
0.7825
Evolutionary model, Frazer et al. Nature 2021. Label at EVE's class25 threshold.
AlphaMissense Pathogenic
0.9984
DeepMind proteome-wide missense predictor
ACMG Points Pathogenic
13
Bayesian point system (threshold 10), 13 achieved
GENIE Carriers Absent
0 / 20,739
Not observed in the 20,739 GENIE v19.0 myeloid samples whose panel covers EZH2
Novel Discovery
EZH2 V662A has never been described in the scientific literature. A
comprehensive search across PubMed, Semantic Scholar, and ClinVar
returns zero results for "EZH2 V662A" or "EZH2 V662."
Among 314 EZH2 papers in the literature corpus, none report
this specific variant.
The variant is absent from gnomAD v4 (0 alleles across ~1.6 million alleles) and absent from GENIE v19.0 (0 carriers among the 20,739 myeloid samples whose panel covers EZH2, see the denominator table).
ClinVar holds one record for this variant: VCV003373649.1, submitted by GeneDx and classified as a variant of uncertain significance (germline, condition not provided), last evaluated March 2024. It carries no functional evidence, no disease context and no supporting publications. This project's submission is prepared but is not yet a public record: the submitting-organisation registration (SUB16087716) is pending approval.
The variant has never been described in the indexed literature and has never been characterised in a somatic or myeloid context, in a gene that has been studied extensively for over 15 years in myeloid malignancies.
The variant is absent from gnomAD v4 (0 alleles across ~1.6 million alleles) and absent from GENIE v19.0 (0 carriers among the 20,739 myeloid samples whose panel covers EZH2, see the denominator table).
ClinVar holds one record for this variant: VCV003373649.1, submitted by GeneDx and classified as a variant of uncertain significance (germline, condition not provided), last evaluated March 2024. It carries no functional evidence, no disease context and no supporting publications. This project's submission is prepared but is not yet a public record: the submitting-organisation registration (SUB16087716) is pending approval.
The variant has never been described in the indexed literature and has never been characterised in a somatic or myeloid context, in a gene that has been studied extensively for over 15 years in myeloid malignancies.
Computational Pathogenicity
| Model | Score | Classification | Reference |
|---|---|---|---|
| EVE | 0.7825 | Uncertain (at EVE's class25 threshold) | Frazer et al. Nature 2021 |
| AlphaMissense | 0.9984 | Pathogenic | Cheng et al. Science 2023 |
| CADD | 28.1 | Deleterious (threshold 25.3) | Rentzsch et al. Nucleic Acids Res 2019 |
| REVEL | 0.781 | Pathogenic (threshold 0.644) | Ioannidis et al. Am J Hum Genet 2016 |
| ESM-2 LLR | -2.966 | PP3 Supporting | Lin et al. Science 2023 |
| SIFT | 0.0 | Damaging | Ng & Henikoff 2003 |
| PolyPhen-2 | 0.992 | Probably damaging | Adzhubei et al. 2010 |
6 of 7 independent computational models classify EZH2 V662A as pathogenic or damaging, giving PP3_VeryStrong. EVE does not: EVE returns 0.7825, which its own class25 calibration (25th/75th percentile ClinVar calibration (recommended)) labels Uncertain. CADD and REVEL are the Ensembl VEP CADD v1.7 values.
SET Domain Loss-of-Function
V662A falls within the catalytic SET domain (residues 612 to 727,
UniProt Q15910) of EZH2, the enzymatic subunit of the Polycomb
Repressive Complex 2 (PRC2). This domain is responsible for
trimethylation of histone H3 at lysine 27 (H3K27me3), a critical
epigenetic silencing mark.
Chase et al. 10
Ernst et al. 9
Chase et al. 10
[10] A 2020
Mutational mechanisms of EZH2 inactivation in myeloid neoplasms. Leukemia (2020)
demonstrated that missense mutations
in the EZH2 SET domain in myeloid neoplasms cause loss-of-function,
reducing H3K27me3 levels. This is the opposite mechanism from lymphoid
malignancies (DLBCL), where EZH2 gain-of-function mutations at Y646
increase H3K27me3. The tissue-specific directionality is critical for
therapeutic decisions.
Ernst et al. 9
[9] T 2010
Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet (2010)
first described EZH2 inactivating
mutations in myeloid disorders (2010, 1,195 citations). The myeloid
context is now well established: EZH2 acts as a tumor suppressor, and
loss-of-function mutations contribute to disease through derepression
of Polycomb target genes.
Tazemetostat: CONTRAINDICATED
Tazemetostat (Tazverik) is an EZH2 inhibitor FDA-approved for
gain-of-function EZH2 mutations in follicular lymphoma and epithelioid
sarcoma. It works by inhibiting EZH2 enzymatic activity.
EZH2 V662A is a loss-of-function mutation. Tazemetostat inhibits the very activity that is already lost. Administering it would further reduce residual H3K27me3, potentially worsening the epigenetic dysregulation.
This is not a theoretical concern. Tazemetostat was voluntarily withdrawn from the U.S. market on March 9, 2026, and the distinction between gain-of-function (lymphoid) and loss-of-function (myeloid) EZH2 mutations is fundamental to the biology 10
Clinical implication: Any clinician seeing "EZH2 mutation" in a myeloid patient must verify the functional consequence before considering EZH2-targeted therapy. The mutation name alone is insufficient; the mechanism (GoF vs LoF) determines whether therapy helps or harms.
EZH2 V662A is a loss-of-function mutation. Tazemetostat inhibits the very activity that is already lost. Administering it would further reduce residual H3K27me3, potentially worsening the epigenetic dysregulation.
This is not a theoretical concern. Tazemetostat was voluntarily withdrawn from the U.S. market on March 9, 2026, and the distinction between gain-of-function (lymphoid) and loss-of-function (myeloid) EZH2 mutations is fundamental to the biology 10
[10] A 2020
Mutational mechanisms of EZH2 inactivation in myeloid neoplasms. Leukemia (2020)
.
Clinical implication: Any clinician seeing "EZH2 mutation" in a myeloid patient must verify the functional consequence before considering EZH2-targeted therapy. The mutation name alone is insufficient; the mechanism (GoF vs LoF) determines whether therapy helps or harms.
Reclassification: VUS to Pathogenic
EZH2 V662A was initially classified as a Variant of Uncertain
Significance (VUS) due to the absence of direct functional assay data
(PS3 at Supporting level only, no definitive functional study of V662A
specifically).
Re-running the ACMG aggregation against the current evidence files gives Pathogenic at 13 Bayesian points (threshold 10). The evidence lines it draws on, and the points each one contributes, are listed in the table below.
The computational evidence line is PP3_VeryStrong, on 6/7 concordant predictors: AlphaMissense 0.9984, CADD 28.1, REVEL 0.781, ESM-2 LLR -2.966, SIFT and PolyPhen-2. EVE is the dissenting tool at 0.7825, which its own class25 calibration labels Uncertain. The strength is driven by AlphaMissense, which clears the Very Strong threshold on its own, so it does not depend on the EVE vote.
With this classification the patient profile changes from 4 confirmed drivers + 1 VUS to 5 confirmed pathogenic drivers, establishing the profile as a quintuple rather than a quadruple co-occurrence.
Re-running the ACMG aggregation against the current evidence files gives Pathogenic at 13 Bayesian points (threshold 10). The evidence lines it draws on, and the points each one contributes, are listed in the table below.
The computational evidence line is PP3_VeryStrong, on 6/7 concordant predictors: AlphaMissense 0.9984, CADD 28.1, REVEL 0.781, ESM-2 LLR -2.966, SIFT and PolyPhen-2. EVE is the dissenting tool at 0.7825, which its own class25 calibration labels Uncertain. The strength is driven by AlphaMissense, which clears the Very Strong threshold on its own, so it does not depend on the EVE vote.
With this classification the patient profile changes from 4 confirmed drivers + 1 VUS to 5 confirmed pathogenic drivers, establishing the profile as a quintuple rather than a quadruple co-occurrence.
| ACMG Criterion | Strength | Points | Evidence |
|---|---|---|---|
| PP3 | Very Strong | 8 | 6/7 pathogenic: AlphaMissense=0.9984 (PP3_VeryStrong), CADD=28.1, REVEL=0.781, ESM-2 LLR=-2.966, EVE=0.7825 (Uncertain), SIFT=0.0, PolyPhen-2=0.992 |
| PM1 | Moderate | 2 | Catalytic SET domain (612-727). Critical for H3K27 methyltransferase activity. |
| PS3 | Supporting | 1 | V662A in catalytic SET domain (612-727). Loss-of-function reducing H3K27me3. EZH2 LOF established as tumor suppressor in myeloid lineage. Ernst 2010, Nikoloski 2010. No direct functional assay for V662A specifically (PS3 at Supporting level). |
| PM2 | Supporting | 1 | Absent from gnomAD v4 (AC=0). Completely absent from gnomAD (0 alleles across exomes + genomes) |
| PM5 | Supporting | 1 | Other missense variants in the EZH2 SET domain (e.g., Y646, A682, A692) are established as pathogenic in lymphoid malignancies (gain-of-function). In myeloid context, EZH2 LOF missense across SET domain are recurrent. |
| Total | 13 | Pathogenic (threshold: 10) |
ACMG/AMP Bayesian point system (Tavtigian et al. Hum Mutat 2020). Richards et al. Genet Med 2015. Rows are read from acmg_aggregation.json as regenerated on 2026-09-20; no value on this page is entered by hand.
PRC2: The 6th Convergence Axis
With EZH2 V662A classified Pathogenic, the patient's mutation profile
spans 6 biological convergence axes, not 5:
1. DNA methylation (DNMT3A R882H)
2. Metabolic (IDH2 R140Q, 2-HG production)
3. PP2A tumor suppression (SETBP1 G870S)
4. RAS-MAPK signaling (PTPN11 E76Q)
5. Cytogenetic (monosomy 7)
6. Chromatin remodeling / PRC2 (EZH2 V662A)
The PRC2 axis is mechanistically distinct from the DNA methylation axis (DNMT3A) and the metabolic axis (IDH2). While all three affect the epigenetic landscape, they operate through independent biochemical pathways: CpG methylation, histone H3K27 trimethylation, and alpha-ketoglutarate-dependent dioxygenase inhibition, respectively.
This 6-axis convergence on a single patient is, to our knowledge, unprecedented in the myeloid genomics literature.
1. DNA methylation (DNMT3A R882H)
2. Metabolic (IDH2 R140Q, 2-HG production)
3. PP2A tumor suppression (SETBP1 G870S)
4. RAS-MAPK signaling (PTPN11 E76Q)
5. Cytogenetic (monosomy 7)
6. Chromatin remodeling / PRC2 (EZH2 V662A)
The PRC2 axis is mechanistically distinct from the DNA methylation axis (DNMT3A) and the metabolic axis (IDH2). While all three affect the epigenetic landscape, they operate through independent biochemical pathways: CpG methylation, histone H3K27 trimethylation, and alpha-ketoglutarate-dependent dioxygenase inhibition, respectively.
This 6-axis convergence on a single patient is, to our knowledge, unprecedented in the myeloid genomics literature.
EZH2 Literature Landscape
| Query | Hits |
|---|---|
| EZH2 V662A | 0 |
| EZH2 V662 | 0 |
| EZH2 loss-of-function myeloid | 100 |
| EZH2 mutation MDS AML | 100 |
| PRC2 myeloid malignancy | 77 |
| EZH2 monosomy 7 | 61 |
| EZH2 SET domain missense | 22 |
Semantic Scholar query results. 314 unique papers across all EZH2-related queries.
The EZH2 literature is extensive (314 unique papers), with
landmark studies including Ernst et al.
9
Ball et al. 11
[9] T 2010
Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet (2010)
(1,195 citations, first description
of EZH2 inactivation in myeloid disorders) and Chase et al.
10[10] A 2020
Mutational mechanisms of EZH2 inactivation in myeloid neoplasms. Leukemia (2020)
(SET domain LoF mechanism).
Ball et al. 11
[11] S 2023
Clinical characteristics and outcomes of EZH2-mutant myelodysplastic syndrome. Leuk Res (2023)
showed that EZH2-mutant MDS with
chromosome 7 abnormalities carries the worst survival among
EZH2-mutant subgroups. This patient has both: EZH2 V662A on monosomy
7, placing them in the highest-risk EZH2 category.
Clinical Implications
Classifying EZH2 V662A as Pathogenic has three immediate
clinical consequences:
1. Tazemetostat contraindication. Any EZH2-targeted therapy designed to inhibit EZH2 activity is contraindicated. The enzymatic activity is already lost.
2. Prognostic impact. EZH2 LoF mutations with chromosome 7 abnormalities carry inferior survival 11
3. Profile rarity. With 5 confirmed pathogenic drivers, the quintuple expected frequency drops to ~7.7×10-13, approximately 1 in 1.3 trillion. The profile was already unprecedented as a quadruple; as a quintuple it is genuinely unknown territory for prognostic modeling.
A ClinVar submission for EZH2 V662A has been prepared based on this computational analysis, with documentation that the classification rests on in silico evidence (PP3_VeryStrong) rather than direct functional assay data. It is not yet a public record: the submitting-organisation registration (SUB16087716) is pending approval. The existing record for this variant remains VCV003373649.1, GeneDx's germline VUS of March 2024.
1. Tazemetostat contraindication. Any EZH2-targeted therapy designed to inhibit EZH2 activity is contraindicated. The enzymatic activity is already lost.
2. Prognostic impact. EZH2 LoF mutations with chromosome 7 abnormalities carry inferior survival 11
[11] S 2023
Clinical characteristics and outcomes of EZH2-mutant myelodysplastic syndrome. Leuk Res (2023)
. This is the worst subgroup within
EZH2-mutant MDS.
3. Profile rarity. With 5 confirmed pathogenic drivers, the quintuple expected frequency drops to ~7.7×10-13, approximately 1 in 1.3 trillion. The profile was already unprecedented as a quadruple; as a quintuple it is genuinely unknown territory for prognostic modeling.
A ClinVar submission for EZH2 V662A has been prepared based on this computational analysis, with documentation that the classification rests on in silico evidence (PP3_VeryStrong) rather than direct functional assay data. It is not yet a public record: the submitting-organisation registration (SUB16087716) is pending approval. The existing record for this variant remains VCV003373649.1, GeneDx's germline VUS of March 2024.
References
- Ernst T, Chase AJ, Score J, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet (2010). PubMed
- Chase A, Score J, Lin F, et al. Mutational mechanisms of EZH2 inactivation in myeloid neoplasms. Leukemia (2020). PubMed
- Ball S, Aguirre LE, Jain AG, et al. Clinical characteristics and outcomes of EZH2-mutant myelodysplastic syndrome. Leuk Res (2023). PubMed
- Frazer J, Notin P, Dias M, et al. Disease variant prediction with deep generative models of evolutionary data. Nature (2021). PubMed
- Cheng J, Novati G, Pan J, et al. Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science (2023). PubMed
- Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants. Genet Med (2015). PubMed
- Tavtigian SV, Harrison SM, Boucher KM, Biesecker LG. Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines. Hum Mutat (2020). PubMed