About EZH2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
EZH2 c.1937A>T, p.(Tyr646Phe)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PS3Strong
PS3 · strong
Well-established functional studies from four independent publications demonstrate that the p.Tyr646Phe (Y641F) alteration causes a gain-of-function effect: altered substrate specificity with increased H3K27 trimethylation activity (PMID:20081860, PMID:21078963, PMID:21190999) and resistance to Jak2/β-TrCP-mediated degradation with increased protein stability (PMID:24469040). Multiple orthogonal functional assays (in vitro methyltransferase assays, cell-based H3K27me3 quantification, protein stability/degradation assays) consistently support a damaging effect on the EZH2 protein.
PM1Moderate
PM1 · moderate
The p.Tyr646Phe variant is located in the SET domain of EZH2 (residues 613-727), a well-established critical functional domain responsible for histone methyltransferase activity. Position 646 is a known mutational hotspot in both somatic cancer (COSMIC, Cancer Hotspots) and is within a region where benign variation is not observed. Multiple publications confirm that this residue is recurrently altered in disease.
PM2Supporting
PM2 · supporting
The variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), indicating it is not observed in large population databases and supporting a pathogenic role.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 strong, PM1 moderate, PM2 supporting; combination = 1 strong + 1 moderate + 1 supporting, which maps to Likely Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
143 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV57445929, n = 143 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
27 criteria with recorded statuses: 3 met · 6 not met · 11 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The NM_004456.5:c.1937A>T (p.Tyr646Phe) variant in EZH2 is absent from large population databases including gnomAD v2.1 and v4.1, consistent with a rare pathogenic variant (PM2_Supporting).
The variant affects Tyr646 in the SET domain of EZH2, the critical catalytic domain responsible for histone H3K27 methyltransferase activity. This residue is a well-established mutational hotspot recurrently altered in B-cell lymphomas, and benign variation at this position is not observed (PM1).
Multiple independent functional studies from four publications demonstrate that the p.Tyr646Phe (also known as Y641F) alteration produces a gain-of-function effect: altered substrate specificity leading to increased H3K27 trimethylation in vitro and in vivo (Morin et al. 2010, Sneeringer et al. 2010, Yap et al. 2011), and resistance to Jak2/β-TrCP-mediated degradation resulting in enhanced protein stability (Sahraeian et al. 2014). These well-established functional assays consistently support a damaging effect on the EZH2 protein (PS3_Strong).
In silico predictions are discordant: REVEL predicts a pathogenic effect (0.853) while BayesDel predicts a benign effect (0.139). SpliceAI predicts no splicing impact (max delta 0.01). These mixed computational predictions do not meet the threshold for either PP3 or BP4.
Overall classification: Likely Pathogenic. Using generic ACMG/AMP 2015 combination rules (PMID:25741868), the evidence profile of 1 Strong (PS3) + 1 Moderate (PM1) + 1 Supporting (PM2) satisfies the Likely Pathogenic threshold (1 Strong AND 1-2 Moderate).
No criteria match.
Met · 3
PS3 StrongWell-established functional studies from four independent publications demonstrate that the p.Tyr646Phe (Y641F) alteration causes a gain-of-function effect: altered substrate specificity with increased H3K27 trimethylation activity (PMID:20081860, PMID:21078963, PMID:21190999) and resistance to Jak2/β-TrCP-mediated degradation with increased protein stability (PMID:24469040). Multiple orthogonal functional assays (in vitro methyltransferase assays, cell-based H3K27me3 quantification, protein stability/degradation assays) consistently support a damaging effect on the EZH2 protein. Details ▾Hide ▴
Evidence considered
- PMID:20081860: demonstrated Y641F alters EZH2 enzymatic activity with reduced monomethylation but altered substrate preference.
- PMID:21078963: demonstrated Y641F has decreased monomethylation but enhanced di-/trimethylation catalytic efficiency relative to wild-type
- with increased H3K27me3 in cells.
- PMID:21190999: demonstrated Y641F acts dominantly to increase H3K27 trimethylation in lymphoma cells
- EZH2-Y641F expression in cells with wild-type EZH2 resulted in increased H3K27me3 in vivo.
- PMID:24469040: demonstrated Y641F prevents Jak2/β-TrCP-mediated degradation
- leading to increased EZH2 protein stability and elevated H3K27me3.
Still missing
- Functional studies were performed in somatic/cancer (lymphoma) context
- direct germline-relevant functional data (e.g.
- developmental assays) are not available.
Sources
PM1 ModerateThe p.Tyr646Phe variant is located in the SET domain of EZH2 (residues 613-727), a well-established critical functional domain responsible for histone methyltransferase activity. Position 646 is a known mutational hotspot in both somatic cancer (COSMIC, Cancer Hotspots) and is within a region where benign variation is not observed. Multiple publications confirm that this residue is recurrently altered in disease. Details ▾Hide ▴
Evidence considered
- Residue Y646 is in the SET domain
- the catalytic domain of EZH2.
- Cancer Hotspots identifies this residue as statistically significant for mutation.
- COSMIC: 143 somatic observations at this residue across lymphoma subtypes.
- PMID:20081860 and PMID:21190999 confirm recurrent somatic mutation at this residue in B-cell lymphomas.
Sources
PM2 SupportingThe variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), indicating it is not observed in large population databases and supporting a pathogenic role. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (0 alleles).
- gnomAD v4.1: absent (0 alleles).
Sources
Not met · 6 · evaluated, threshold not reached
PP3 In silico predictions are discordant: REVEL predicts a pathogenic effect (score 0.853, above the >0.5 threshold), but BayesDel predicts a benign effect (score 0.139, below the >0.27 pathogenic threshold). SpliceAI predicts no splicing impact (max delta 0.01). Multiple lines of computational evidence do not consistently support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.853 (pathogenic).
- BayesDel score: 0.138559 (benign-leaning).
- SpliceAI max delta: 0.01 (no splice impact).
Sources
BA1 The variant is absent from gnomAD v2.1 and v4.1. BA1 requires an allele frequency >1% in any population, which is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF: absent
- gnomAD v4.1 AF: absent. Does not reach the BA1 threshold of >1%.
Sources
BS1 The variant is absent from gnomAD v2.1 and v4.1. BS1 requires an allele frequency >0.3%, which is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF: absent
- gnomAD v4.1 AF: absent. Does not reach the BS1 threshold of >0.3%.
Sources
BS3 Well-established functional studies demonstrate a gain-of-function damaging effect for p.Tyr646Phe (Y641F), including increased H3K27 trimethylation and enhanced protein stability. BS3 requires functional studies showing no damaging effect, which is contradicted by the available evidence. Details ▾Hide ▴
Evidence considered
- PMID:20081860
- PMID:21078963
- PMID:21190999
- PMID:24469040 all demonstrate gain-of-function or altered protein function for Y641F.
- Functional evidence supports a damaging effect
- not a benign one.
Sources
BP1 BP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. EZH2-related Weaver syndrome is primarily caused by missense variants; early truncating mutations are notably absent, with a proposed dominant-negative rather than haploinsufficiency mechanism. BP1 is not applicable to this gene. Details ▾Hide ▴
Evidence considered
- EZH2 Weaver syndrome is caused by heterozygous missense mutations
- truncating variants are not the primary disease mechanism.
- PMID:40846643: 'lack of early truncating mutations in EZH2 led us to hypothesize a dominant-negative mechanism for WS.'
Sources
pvs1_gene_context
BP4 Multiple lines of computational evidence do not consistently suggest no impact. REVEL score is 0.853 (pathogenic), contradicting a benign interpretation. BayesDel score is 0.139 (benign-leaning) but does not override the strongly pathogenic REVEL prediction. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.853 (pathogenic).
- BayesDel score: 0.139 (benign-leaning).
- Computational evidence is discordant
- does not support a benign interpretation.
Sources
Not assessed · 11 · no assessment recorded
PS2 No de novo occurrence data (with confirmed maternity/paternity) was available for this variant. The exploratory evidence search for de novo reports failed to return usable results. Details ▾Hide ▴
Evidence considered
- Exploratory sub-agent search for PS2 evidence failed (exploratory_result.failed.json). No de novo reports identified.
Still missing
- De novo occurrence data not available
- could be investigated through clinical testing laboratories or trio sequencing databases.
PS4 No case-control or cohort data comparing variant prevalence in affected individuals versus controls for a germline phenotype is available. The variant has been reported 143 times in COSMIC (somatic cancer), but these are somatic observations not suitable for PS4 in a germline context. Details ▾Hide ▴
Evidence considered
- COSMIC: 143 somatic observations. No germline case-control data available.
Still missing
- Germline case-control or cohort enrichment data not available.
PM6 No confirmed de novo report for this specific variant was identified. The exploratory evidence search did not return usable de novo data. Details ▾Hide ▴
Evidence considered
- Exploratory sub-agent search for PM6 evidence failed. No de novo case reports for NM_004456.5:c.1937A>T identified.
Still missing
- De novo event data not available
- could be investigated through clinical testing databases.
PP1 No segregation data (co-segregation of the variant with disease in multiple affected family members) is available for this variant. Details ▾Hide ▴
Evidence considered
- No family segregation studies identified for this variant.
Still missing
- Segregation analysis in affected families not available.
PP2 While EZH2 missense variants are a known mechanism of Weaver syndrome (a germline overgrowth disorder), gnomAD missense constraint metrics (Z-score, o/e ratio) were not retrieved to confirm a low rate of benign missense variation in this gene. Both conditions of PP2 must be met to apply this criterion. Details ▾Hide ▴
Evidence considered
- EZH2 germline missense variants cause Weaver syndrome (per PVS1 gene context)
- but population-level missense constraint data are not available in the evidence brief.
Still missing
- gnomAD missense constraint metrics (Z-score
- o/e ratio) not retrieved
- needed to confirm low rate of benign missense variation in EZH2.
PP4 No patient phenotype or family history information is available for this case to assess whether the clinical presentation is highly specific for EZH2-related disease. Details ▾Hide ▴
Evidence considered
- No proband phenotype or family history data provided in the case.
Still missing
- Patient phenotype and family history information not available for assessment.
BS2 No data are available regarding observation of this variant in a homozygous or hemizygous state in healthy adults with full penetrance expected at an early age. Details ▾Hide ▴
Evidence considered
- No homozygous/hemizygous observations in gnomAD or other sources.
Still missing
- Observation in healthy homozygous/hemizygous individuals not available.
BS4 No segregation data are available to evaluate lack of segregation of the variant with disease in affected family members. Details ▾Hide ▴
Evidence considered
- No family-based segregation analysis available.
Still missing
- Family segregation data not available.
BP2 No data are available regarding observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant. Details ▾Hide ▴
Evidence considered
- No phase information available for this variant.
Still missing
- Phase information (cis/trans with other variants) not available.
BP5 No data are available regarding observation of this variant in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternate molecular diagnosis data available.
Still missing
- Alternate molecular diagnosis data not available.
BP6 No reputable source has reported this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no benign classification by any submitter.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Tyr646Phe) that does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Details ▾Hide ▴
Evidence considered
- Missense substitution
- variant_bucket=other per pvs1_variant_assessment
- apply_generic_pvs1_framework=false.
Sources
PS1 N/ANo previously classified pathogenic variant with the same amino acid change (p.Tyr646Phe) was identified in ClinVar or the curated literature to support PS1. Details ▾Hide ▴
Evidence considered
- This variant is absent from ClinVar
- no same-change pathogenic comparator exists.
Sources
PM5 N/ANo previously classified pathogenic missense variant at the same amino acid residue (Tyr646) with a different amino acid change was identified in ClinVar. PM5 candidate harvesting found zero same-residue comparators. Details ▾Hide ▴
Evidence considered
- Zero same-residue comparator variants found
- no expert-panel P/LP calls at residue 646 with a different amino acid change.
Sources
pm5_candidates
PP5 N/ANo reputable source (e.g., clinical diagnostic laboratory, expert panel) has reported this variant as pathogenic without the evidence being available for independent evaluation. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no prior classification by any submitter.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not an in-frame indel in a repetitive region.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a missense variant (c.1937A>T, p.Tyr646Phe), not a synonymous change. Details ▾Hide ▴
Evidence considered
- Missense substitution at coding position 1937
- not a synonymous variant.
PS5 N/AThis variant is not reported as a de novo occurrence (PS2 prerequisite not met), so PS5 cannot be applied. Details ▾Hide ▴
Evidence considered
- PS5 requires prior de novo observation (PS2)
- which is not established for this variant.
Identifiers
- Gene
- EZH2
- Transcript
- NM_004456.5
- Coding (HGVS c.)
- NM_004456.5:c.1937A>T
- Protein (HGVS p.)
- NP_004447.2:p.(Tyr646Phe)
- GRCh38
- chr7:148811635 T>A
- GRCh37
- chr7:148508727 T>A
- COSMIC
- COSV57445929
Gene diagram
Every interpreted variant in EZH2, mapped onto the exon structure of NM_004456.5. Select a row to find it on the plot.
EZH2NM_004456.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in EZH2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.853
- BayesDel
- 0.139
How the predictions were used
PP3 In silico predictions are discordant: REVEL predicts a pathogenic effect (score 0.853, above the >0.5 threshold), but BayesDel predicts a benign effect (score 0.139, below the >0.27 pathogenic threshold). SpliceAI predicts no splicing impact (max delta 0.01). Multiple lines of computational evidence do not consistently support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.853 (pathogenic).
- BayesDel score: 0.138559 (benign-leaning).
- SpliceAI max delta: 0.01 (no splice impact).
Sources
BP4 Multiple lines of computational evidence do not consistently suggest no impact. REVEL score is 0.853 (pathogenic), contradicting a benign interpretation. BayesDel score is 0.139 (benign-leaning) but does not override the strongly pathogenic REVEL prediction. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.853 (pathogenic).
- BayesDel score: 0.139 (benign-leaning).
- Computational evidence is discordant
- does not support a benign interpretation.
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a missense variant (c.1937A>T, p.Tyr646Phe), not a synonymous change. Details ▾Hide ▴
Evidence considered
- Missense substitution at coding position 1937
- not a synonymous variant.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.853. BayesDel score = 0.138559.
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 20081860 ↗Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin.No paper-specific finding is recorded.
-
PMID 21078963 ↗Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas.No paper-specific finding is recorded.
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PMID 21190999 ↗Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation.No paper-specific finding is recorded.
-
PMID 21796119 ↗Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma.No paper-specific finding is recorded.
-
PMID 24469040 ↗Oncogenic Y641 mutations in EZH2 prevent Jak2/β-TrCP-mediated degradation.No paper-specific finding is recorded.
-
PMID 25402979 ↗Gain-of-function mutation of chromatin regulators as a tumorigenic mechanism and an opportunity for therapeutic intervention.No paper-specific finding is recorded.
-
PMID 25671303 ↗Epigenetic reprogramming by tumor-derived EZH2 gain-of-function mutations promotes aggressive 3D cell morphologies and enhances melanoma tumor growth.No paper-specific finding is recorded.
-
PMID 30705065 ↗Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_004456.5%3Ac.1937A%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-148508727-T-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-148811635-T-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004456.5%3Ac.1937…
- OncoKB ↗www.oncokb.org/gene/EZH2/Y646F
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=126525033
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.853. BayesDel score = 0.138559.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57445929, n = 143 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.