About EZH2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
EZH2 c.1797G>A, p.(Trp599Ter)
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
This variant is a nonsense change, p.Trp599Ter, in exon 15 and is followed by multiple downstream coding exons, which is consistent with a premature termination codon expected to trigger nonsense-mediated decay. EZH2 was flagged as eligible for generic loss-of-function assessment, so PVS1 is met under the ClinGen SVI generic PVS1 framework, although human review remains appropriate because no gene-specific specification was available.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the usual PM2 rarity threshold of 0.1% for a rare germline disorder. These population data support PM2 at supporting strength.
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: PVS1 very strong, PM2 supporting; combination = 1 very strong + 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.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
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 Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie 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.
28 criteria with recorded statuses: 2 met · 7 not met · 11 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The EZH2 c.1797G>A (p.Trp599Ter; p.W599*) variant has been reported in ClinVar as a variant of uncertain significance with one clinical laboratory submission.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the usual PM2 population threshold of 0.1% for a rare germline disorder.
This nonsense variant is predicted to introduce a premature termination codon in exon 15 with downstream coding exons remaining, and generic PVS1 review indicates that EZH2 is eligible for loss-of-function assessment under the ClinGen SVI framework.
SpliceAI predicts no significant splice impact for this variant (maximum delta score 0.01), while BayesDel is 0.655873; these computational findings do not provide standalone benign support for this truncating variant.
No criteria match.
Met · 2
PVS1 Very strongThis variant is a nonsense change, p.Trp599Ter, in exon 15 and is followed by multiple downstream coding exons, which is consistent with a premature termination codon expected to trigger nonsense-mediated decay. EZH2 was flagged as eligible for generic loss-of-function assessment, so PVS1 is met under the ClinGen SVI generic PVS1 framework, although human review remains appropriate because no gene-specific specification was available. Details ▾Hide ▴
Evidence considered
- Nonsense variant p.Trp599Ter
- Variant maps to exon 15 with downstream coding exons remaining
- Generic PVS1 eligibility for EZH2 loss-of-function review
Still missing
- No official CSPEC/VCEP or local gene-specific PVS1 rule was available for EZH2.
- Transcript relevance and disease-mechanism interpretation should be confirmed during final review.
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the usual PM2 rarity threshold of 0.1% for a rare germline disorder. These population data support PM2 at supporting strength. Details ▾Hide ▴
Not met · 7 · evaluated, threshold not reached
PS3 Published studies reviewed describe EZH2 loss-of-function biology at the gene level, including somatic mutations and EZH2 deletion models, but they do not provide a well-established functional assay directly testing p.Trp599Ter. Available evidence therefore does not support PS3 for this specific variant. Details ▾Hide ▴
Evidence considered
- Gene-level EZH2 functional literature
- OncoKB-linked functional references
Still missing
- Need a validated functional study directly testing p.Trp599Ter or the exact c.1797G>A variant.
Sources
PS4 This variant has one ClinVar submission and no case-control or recurrence data demonstrating enrichment in affected individuals. Available evidence does not support a statistically increased prevalence in affected individuals, so PS4 is not met. Details ▾Hide ▴
Evidence considered
- Single ClinVar submitter
- Variant absent from gnomAD
Still missing
- Need multiple independent affected observations or case-control enrichment data for this exact variant.
Sources
PM1 This variant has not been shown to lie in a well-established mutational hotspot or critical domain without benign variation. Available hotspot review does not support PM1. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots review did not identify a significant hotspot at W599
Still missing
- Need a validated hotspot or critical-region assignment for this residue.
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is far below the 1% BA1 threshold. BA1 is not met. Details ▾Hide ▴
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the usual BS1 threshold of 0.3%. BS1 is not met. Details ▾Hide ▴
BS3 Published studies reviewed address EZH2 loss-of-function at the gene level, but no well-established functional study was identified showing normal function for p.Trp599Ter. Available evidence does not support BS3 for this variant. Details ▾Hide ▴
Evidence considered
- Gene-level EZH2 functional literature
- OncoKB-linked references
Still missing
- Need a validated functional study directly showing normal function for the exact variant.
Sources
BP4 SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, but BayesDel is 0.655873 and does not support a benign interpretation; no REVEL score was available. Overall, computational evidence does not support a benign effect, so BP4 is not met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01
- BayesDel 0.655873
- No REVEL score found
Still missing
- No REVEL score was available.
Sources
spliceai ↗bayesdel
Not assessed · 11 · no assessment recorded
PS1 No evidence was identified for a different pathogenic nucleotide change that results in the same p.Trp599Ter protein effect, so PS1 was not assessed. Details ▾Hide ▴
Evidence considered
- ClinVar exact-variant record only
Still missing
- Need evidence of another pathogenic variant producing the same amino acid change.
Sources
PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant, so PS2 was not assessed. Details ▾Hide ▴
Evidence considered
- ClinVar submission review found no de novo annotation
Still missing
- Need a case report or database submission documenting confirmed de novo occurrence for this exact variant.
Sources
PM3 No evidence was identified for this variant in trans with another pathogenic variant in an established recessive disease context, so PM3 was not assessed. Details ▾Hide ▴
Evidence considered
- No phasing or second-allele evidence identified
Still missing
- Need phase data and a relevant recessive disease context if PM3 is to be considered.
Sources
PM6 No presumed de novo report without confirmed parentage was identified for this variant, so PM6 was not assessed. Details ▾Hide ▴
Evidence considered
- ClinVar review found no de novo annotation
Still missing
- Need case-level inheritance data indicating de novo occurrence without full parentage confirmation.
Sources
PP1 No segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Evidence considered
- No family segregation information identified
Still missing
- Need informative family data showing co-segregation with disease.
Sources
PP3 SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.01, and BayesDel is 0.655873; no REVEL score was available. These computational findings were reviewed, but PP3 was not applied because this is a clear nonsense variant already addressed through PVS1 rather than a missense or splice-prediction driven interpretation. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01
- BayesDel 0.655873
- No REVEL score found
Still missing
- No REVEL score was available.
- If computational evidence is to be used independently
- a gene- and variant-type appropriate rule would need to be defined.
Sources
spliceai ↗bayesdel
PP4 No patient-specific phenotype information was provided that could be assessed for high specificity to an EZH2-related disorder, so PP4 was not assessed. Details ▾Hide ▴
Evidence considered
- No phenotype-specific case evidence identified
Still missing
- Need detailed clinical phenotype and its specificity for EZH2-related disease.
Sources
BS2 No evidence was identified showing this variant in healthy adults under circumstances sufficient to argue against pathogenicity, so BS2 was not assessed. Details ▾Hide ▴
Evidence considered
- Variant absent from available population datasets
Still missing
- Need well-documented observations in unaffected individuals appropriate for the associated disease context.
Sources
BS4 No non-segregation data were identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Evidence considered
- No discordant family data identified
Still missing
- Need family data showing the variant does not track with disease.
Sources
BP2 No evidence was identified that this variant is observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant in a way that supports BP2, so BP2 was not assessed. Details ▾Hide ▴
Evidence considered
- No co-occurrence data identified
Still missing
- Need phase information and relevant co-occurring pathogenic variant data.
Sources
BP5 No alternate molecular explanation for the relevant phenotype was provided, so BP5 was not assessed. Details ▾Hide ▴
Evidence considered
- No alternate-diagnosis data identified
Still missing
- Need case-level phenotype and alternate-cause evidence if BP5 is to be considered.
Sources
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PM4 N/APM4 addresses protein length changes from in-frame insertions, deletions, or stop-loss variants. This variant is a nonsense change, so PM4 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant classified as nonsense
Sources
pvs1_variant_assessment
PM5 N/APM5 applies to a novel missense change at an amino acid residue where a different pathogenic missense change has been seen. This variant is a nonsense change, so PM5 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant classified as nonsense
Sources
pvs1_variant_assessment
PP2 N/APP2 is used for missense variants in genes where missense variation is a common disease mechanism and benign missense variation is rare. This variant is a nonsense change, so PP2 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant classified as nonsense
Sources
pvs1_variant_assessment
PP5 N/APP5 was not applied. The only ClinVar assertion identified was a single-submitter variant of uncertain significance, and classification was not based on an external assertion alone. Details ▾Hide ▴
BP1 N/ABP1 applies to missense variants in genes where truncating variants are the predominant disease mechanism. This variant is a nonsense change, so BP1 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant classified as nonsense
Sources
pvs1_variant_assessment
BP3 N/ABP3 addresses in-frame insertions or deletions in repetitive regions without known function. This variant is a nonsense substitution, so BP3 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant classified as nonsense substitution
Sources
pvs1_variant_assessment
BP6 N/ABP6 was not applied. No benign or likely benign assertion from a source used without accessible evidence was identified, and the available ClinVar submission is a variant of uncertain significance. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous or certain intronic variants with no predicted splice impact. This variant is a nonsense coding change, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant classified as nonsense
- SpliceAI reviewed but variant is not synonymous or intronic
Sources
spliceai ↗pvs1_variant_assessment
Identifiers
- Gene
- EZH2
- Transcript
- NM_004456.4
- Coding (HGVS c.)
- NM_004456.4:c.1797G>A
- Protein (HGVS p.)
- NP_004447.2:p.(Trp599Ter)
- GRCh38
- chr7:148814013 C>T
- GRCh37
- chr7:148511105 C>T
Gene diagram
Every interpreted variant in EZH2, mapped onto the exon structure of NM_004456.4. Select a row to find it on the plot.
EZH2NM_004456.4
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
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, but BayesDel is 0.655873 and does not support a benign interpretation; no REVEL score was available. Overall, computational evidence does not support a benign effect, so BP4 is not met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01
- BayesDel 0.655873
- No REVEL score found
Still missing
- No REVEL score was available.
Sources
spliceai ↗bayesdel
PP3 SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.01, and BayesDel is 0.655873; no REVEL score was available. These computational findings were reviewed, but PP3 was not applied because this is a clear nonsense variant already addressed through PVS1 rather than a missense or splice-prediction driven interpretation. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01
- BayesDel 0.655873
- No REVEL score found
Still missing
- No REVEL score was available.
- If computational evidence is to be used independently
- a gene- and variant-type appropriate rule would need to be defined.
Sources
spliceai ↗bayesdel
BP7 N/ABP7 applies to synonymous or certain intronic variants with no predicted splice impact. This variant is a nonsense coding change, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant classified as nonsense
- SpliceAI reviewed but variant is not synonymous or intronic
Sources
spliceai ↗pvs1_variant_assessment
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.655873.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
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
Captured SpliceAI source record
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/variation/3906370/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-148511105-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-148814013-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004456.4%3Ac.1797…
- OncoKB ↗www.oncokb.org/gene/EZH2/W599*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=EZH2+c.1797G%3EA
- 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 has been reported in ClinVar as Uncertain significance (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.655873.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.