About EZH2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
EZH2 c.1966G>A, p.(Ala656Thr)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, with an allele frequency of 0. This meets the PM2 threshold for absence from population databases (allele frequency <0.1% for non-VCEP).
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. 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 did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. EZH2, an epigenetic modifier, is altered by mutation and/or overexpression in solid tumors and hematologic malignancies.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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.
26 criteria with recorded statuses: 1 met · 21 not met · 1 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_004456.4:c.1966G>A (p.Ala656Thr) is a missense variant in EZH2 that is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_Supporting).
No additional pathogenic or benign criteria are met. The variant has not been reported in ClinVar, has no functional studies, no segregation data, no de novo observations, and in silico predictors are discordant (REVEL 0.753 damaging; BayesDel 0.311 benign).
With a single supporting criterion (PM2) and no conflicting benign evidence, the variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines (PMID:25741868).
No criteria match.
Met · 1
PM2 SupportingThe variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, with an allele frequency of 0. This meets the PM2 threshold for absence from population databases (allele frequency <0.1% for non-VCEP). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AF=0)
- Absent from gnomAD v4.1 (AF=0)
- Absent from gnomAD-Canada v1.0 (AF=0)
Sources
Not met · 21 · evaluated, threshold not reached
PS1 No prior report of a different nucleotide change at codon 656 resulting in the same p.Ala656Thr missense alteration with a pathogenic classification. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- ClinVar contains no variants at codon 656
- no submissions for this variant
Still missing
- No ClinVar entries at codon 656 to enable PS1 comparison
Sources
PS2 No de novo observation has been reported for this variant. No publications identified through the literature pipeline. Details ▾Hide ▴
Evidence considered
- No de novo reports in literature or databases
Still missing
- No de novo testing data available
PS3 No well-established functional studies demonstrating a damaging effect have been reported for this variant. OncoKB lists the variant as Unknown Oncogenic Effect and no PMIDs with functional data were identified. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no functional PMIDs identified
Still missing
- No functional studies available for this variant
Sources
PS4 No case-control studies or statistical evidence of enrichment in affected individuals versus controls. The variant is absent from ClinVar, so no disease association data exist. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no epidemiological or case-control data
Still missing
- No case-control or cohort studies available
Sources
PM1 The variant does not lie in a statistically significant mutational hotspot as assessed by Cancer Hotspots. No domain-specific enrichment data are available. Codon 656 is in the C-terminal region of EZH2 but has not been established as a critical functional domain for germline disease. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue not significant
- exact variant not listed
Still missing
- No domain-specific hotspot data for germline EZH2 variants
PM6 No de novo observation has been reported for this variant. No publications describing de novo occurrence were identified. Details ▾Hide ▴
Evidence considered
- No de novo reports in literature or databases
Still missing
- No de novo testing data
PP1 No co-segregation data are available for this variant. No family studies have been reported. Details ▾Hide ▴
Evidence considered
- No co-segregation or family studies available
Still missing
- No familial segregation data
PP3 Insufficient consensus among multiple in silico predictors. REVEL score of 0.753 is above the pathogenicity threshold (≥0.5), but BayesDel score of 0.311 is below the damaging threshold (<0.5), and SpliceAI predicts no splicing impact (max delta score 0.02). PP3 requires multiple lines of computational support, which are not met here. Details ▾Hide ▴
Evidence considered
- REVEL: 0.753 (damaging)
- BayesDel: 0.311 (benign)
- SpliceAI max delta: 0.02 (no splicing impact)
Still missing
- Discordant in silico predictions
- only REVEL supports pathogenicity
Sources
PP4 No clinical phenotype or family history data are available to assess whether the patient's presentation is highly specific for EZH2-associated Weaver syndrome. Details ▾Hide ▴
Evidence considered
- No clinical phenotype data provided
Still missing
- No patient phenotype or family history information
PP5 No reputable source has classified this variant as pathogenic. The variant is absent from ClinVar with zero submissions. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no expert panel or clinical laboratory classifications
Still missing
- No ClinVar submissions
Sources
BA1 The variant is absent from gnomAD (allele frequency = 0). Does not meet the BA1 threshold of >1% population frequency. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD datasets (AF=0)
Sources
BS1 The variant is absent from gnomAD (allele frequency = 0). Does not meet the BS1 threshold of >0.3% for rare disease (non-VCEP cutoff). Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD datasets (AF=0)
Sources
BS2 The variant has not been observed in any healthy adult individuals in population databases. No evidence of occurrence with full penetrance expected but absent disease. Details ▾Hide ▴
Evidence considered
- No observation in any individual (healthy or affected) in population databases
Still missing
- No population observations of any kind
BS3 No well-established functional studies demonstrating no deleterious effect have been reported for this variant. Details ▾Hide ▴
Evidence considered
- No functional studies identified for this variant
Still missing
- No functional data
BS4 No segregation data are available to assess lack of segregation with disease in affected families. Details ▾Hide ▴
Evidence considered
- No family segregation data available
Still missing
- No familial segregation studies
BP1 EZH2 Weaver syndrome is primarily caused by missense variants through a dominant-negative mechanism, not by truncating mutations. The literature (PMID:40846643) explicitly notes the lack of early truncating mutations in EZH2 and supports a dominant-negative mechanism for missense variants. BP1 requires that the gene's primary disease mechanism is truncating, which does not apply to EZH2. Details ▾Hide ▴
Evidence considered
- Weaver syndrome is a missense-driven dominant-negative disorder
- truncating mutations are not the primary mechanism
BP2 No observation of this variant in trans with a known pathogenic dominant variant in EZH2. No data available. Details ▾Hide ▴
Evidence considered
- No trans configuration data available
Still missing
- No phase information or trans observations
BP4 Insufficient consensus among multiple in silico predictors for a benign effect. REVEL score of 0.753 indicates a damaging prediction, contradicting the requirement for multiple lines of benign computational evidence. Only BayesDel (0.311) supports a benign interpretation, and SpliceAI (max delta 0.02) is neutral. Details ▾Hide ▴
Evidence considered
- REVEL: 0.753 (damaging
- contradicts benign)
- BayesDel: 0.311 (benign)
- SpliceAI max delta: 0.02 (neutral)
Still missing
- Only one of three in silico tools supports benign prediction
Sources
BP5 No case has been reported in which this variant is found in an individual with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis cases identified
Still missing
- No cases with alternate molecular diagnoses
BP6 No reputable source has classified this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no benign classifications from any source
Still missing
- No ClinVar submissions
Sources
PS5 No pathogenic missense variants have been reported at codon 656 (Ala656) in ClinVar. No comparators exist to satisfy the PS5 requirement of a different pathogenic missense at the same residue. Details ▾Hide ▴
Evidence considered
- ClinVar is empty for codon 656
- PM5 candidate search returned zero candidates
Still missing
- No pathogenic missense variants at codon 656
Sources
clinvar ↗pm5_candidates
Not assessed · 1 · no assessment recorded
PP2 HCI prior score is unavailable for EZH2 (gene not supported by the HCI prior database). Without quantitative data on the gene's benign missense variation rate, PP2 cannot be reliably assessed. Note that EZH2 Weaver syndrome is primarily driven by missense variants (dominant-negative mechanism), but the rate of benign missense variation cannot be determined without HCI prior. Details ▾Hide ▴
Evidence considered
- HCI prior: gene not supported
- no benign missense rate data available
Still missing
- HCI prior score unavailable for EZH2
- cannot quantify benign missense constraint
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Ala656Thr) and does not fall into any PVS1 null-variant category (nonsense, frameshift, or canonical ±1,2 splice consensus). The generic PVS1 decision framework (PMC6185798) confirms this variant is not eligible for PVS1. Details ▾Hide ▴
Evidence considered
- Missense substitution at codon 656
- variant_bucket=other
- apply_generic_pvs1_framework=false
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM5 N/ANo pathogenic missense variants have been identified at the same residue (Ala656) to enable PM5 comparison. Automated ClinVar candidate harvesting for codon 656 returned zero candidates. Details ▾Hide ▴
Evidence considered
- Zero same-residue candidates
- zero expert panel P/LP candidates
- PM5 mode=unknown
Sources
pm5_candidates
BP7 N/AThis is a missense variant (p.Ala656Thr), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. SpliceAI predicts no splicing impact (max delta 0.02), but the criterion is fundamentally inapplicable to missense variants. Details ▾Hide ▴
Evidence considered
- Missense substitution
- BP7 is restricted to synonymous variants
Identifiers
- Gene
- EZH2
- Transcript
- NM_004456.4
- Coding (HGVS c.)
- NM_004456.4:c.1966G>A
- Protein (HGVS p.)
- NP_004447.2:p.(Ala656Thr)
- GRCh38
- chr7:148810396 C>T
- GRCh37
- chr7:148507488 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
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.753
- BayesDel
- 0.311
How the predictions were used
PP3 Insufficient consensus among multiple in silico predictors. REVEL score of 0.753 is above the pathogenicity threshold (≥0.5), but BayesDel score of 0.311 is below the damaging threshold (<0.5), and SpliceAI predicts no splicing impact (max delta score 0.02). PP3 requires multiple lines of computational support, which are not met here. Details ▾Hide ▴
Evidence considered
- REVEL: 0.753 (damaging)
- BayesDel: 0.311 (benign)
- SpliceAI max delta: 0.02 (no splicing impact)
Still missing
- Discordant in silico predictions
- only REVEL supports pathogenicity
Sources
BP4 Insufficient consensus among multiple in silico predictors for a benign effect. REVEL score of 0.753 indicates a damaging prediction, contradicting the requirement for multiple lines of benign computational evidence. Only BayesDel (0.311) supports a benign interpretation, and SpliceAI (max delta 0.02) is neutral. Details ▾Hide ▴
Evidence considered
- REVEL: 0.753 (damaging
- contradicts benign)
- BayesDel: 0.311 (benign)
- SpliceAI max delta: 0.02 (neutral)
Still missing
- Only one of three in silico tools supports benign prediction
Sources
BP7 N/AThis is a missense variant (p.Ala656Thr), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. SpliceAI predicts no splicing impact (max delta 0.02), but the criterion is fundamentally inapplicable to missense variants. Details ▾Hide ▴
Evidence considered
- Missense substitution
- BP7 is restricted to synonymous variants
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.753. BayesDel score = 0.311152.
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
Recorded maximum delta 0.020
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_004456.4%3Ac.1966G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-148507488-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-148810396-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-148810396-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004456.4%3Ac.1966…
- OncoKB ↗www.oncokb.org/gene/EZH2/A656T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=EZH2+c.1966G%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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.753. BayesDel score = 0.311152.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. EZH2, an epigenetic modifier, is altered by mutation and/or overexpression in solid tumors and hematologic malignancies.
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.