EZH2 c.698A>G, p.Asp233Gly
NM_004456.4:c.698A>G
Variant of Uncertain Significance (VUS)
The variant NM_004456.4:c.698A>G (D233G) in EZH2 is absent from population databases (PM2, Moderate) and multiple computational tools predict a deleterious effect (PP3, Supporting). No other criteria are met or evaluable. Therefore, the variant remains classified as a Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM3
PP4
Genetic Information
Gene & Transcript Details
Gene
EZH2
Transcript
NM_004456.5
MANE Select
Total Exons
20
Strand
Reverse (−)
Reference Sequence
NC_000007.13
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_004456.4 | RefSeq Select | 20 exons | Reverse |
| NM_004456.3 | Alternative | 20 exons | Reverse |
Variant Details
HGVS Notation
NM_004456.4:c.698A>G
Protein Change
D233G
Location
Exon 7
(Exon 7 of 20)
5'Exon Structure (20 total)3'
Functional Consequence
Missense Variant
Related Variants
No evidence of other pathogenic variants at position 233 in gene EZH2
Variant interpretation based on transcript NM_004456.5
Genome Browser
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HGVS InputNM_004456:c.698A>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 233 in gene EZH2
Functional Summary
The EZH2 D233G variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.784
0.784
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 7.60
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: 'PVS1 – Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)'. The evidence for this variant shows it is a missense change (D233G), not a null variant. Therefore, this criterion is not applied because the variant type does not meet the rule.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'PS1 – Same amino acid change as a known pathogenic variant but different nucleotide change'. The evidence for this variant shows no previously established pathogenic variant at residue D233. Therefore, this criterion is not applied because there is no matching known pathogenic amino acid change.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'PS2 – De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. The evidence for this variant shows no data on de novo status. Therefore, this criterion is not applied due to lack of de novo confirmation.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: 'PS3 – Well-established functional studies supportive of a damaging effect on the gene or gene product'. The evidence for this variant shows no functional study data. Therefore, this criterion is not applied because functional studies are lacking.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'PS4 – Prevalence in affected individuals significantly increased compared with controls'. The evidence for this variant shows no case-control or prevalence data. Therefore, this criterion is not applied due to absence of prevalence data.
PM2
PM2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'PM1 – Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence for this variant shows no information on hotspot or domain. Therefore, this criterion is not applied due to lack of domain annotation.
PM3
PM3 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'PM2 – Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows it is absent from population databases (gnomAD MAF=0%). Therefore, this criterion is applied at Moderate strength because the variant is not present in controls.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'PM3 – Detected in trans with a pathogenic variant (for recessive disorders)'. The evidence for this variant shows no data on trans phase with another variant. Therefore, this criterion is not applied due to absence of phase data.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'PM4 – Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence for this variant shows a single amino acid substitution with no length change. Therefore, this criterion is not applied because there is no protein length alteration.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: 'PM5 – Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The evidence for this variant shows no other pathogenic changes reported at D233. Therefore, this criterion is not applied because there is no known pathogenic variant at the same residue.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'PM6 – Assumed de novo, but without confirmation of paternity and maternity'. The evidence for this variant shows no de novo data. Therefore, this criterion is not applied due to lack of assumed de novo evidence.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'PP1 – Co-segregation with disease in multiple affected family members'. The evidence for this variant shows no segregation data. Therefore, this criterion is not applied because family segregation information is unavailable.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'PP2 – Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease'. The evidence for this variant does not include gene-specific missense constraint data. Therefore, this criterion is not applied due to lack of supportive gene-level evidence.
PP4
PP4 (Supporting)
According to standard ACMG guidelines, the rule for PP3 is: 'PP3 – Multiple lines of computational evidence support a deleterious effect on the gene/gene product (e.g., conservation, splicing impact)'. The evidence for this variant shows high REVEL score (0.78), damaging predictions from PolyPhen-2, MetaSVM, MetaLR, PrimateAI, and SpliceAI impact score (0.99). Therefore, this criterion is applied at Supporting strength because multiple in silico tools predict a deleterious effect.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'PP4 – Patient's phenotype or family history highly specific for a disease with a single genetic etiology'. The evidence for this variant shows no phenotype or family history data. Therefore, this criterion is not applied due to absence of specific clinical information.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'PP5 – Reputable source reports variant as pathogenic, but without accessible evidence'. The evidence for this variant shows no reports in ClinVar or other sources. Therefore, this criterion is not applied because no reputable pathogenic assertion exists.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'BA1 – Allele frequency is too high for the disorder (based on population data)'. The evidence for this variant shows MAF=0% in gnomAD. Therefore, this criterion is not applied because the allele frequency is not above threshold.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'BS1 – Allele frequency is greater than expected for the disorder'. The evidence for this variant shows no presence in population databases. Therefore, this criterion is not applied because the allele frequency does not exceed expected limits.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'BS2 – Observed in healthy individuals with full penetrance expected at an early age'. The evidence for this variant shows no observation in healthy individuals. Therefore, this criterion is not applied due to lack of healthy adult data.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: 'BS3 – Well-established functional studies show no damaging effect on protein function or splicing'. The evidence for this variant shows no functional data. Therefore, this criterion is not applied because studies demonstrating benign effect are unavailable.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'BS4 – Lack of segregation in affected family members'. The evidence for this variant shows no segregation analysis. Therefore, this criterion is not applied due to absence of segregation data.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'BP1 – Missense variant in a gene where only LoF causes disease'. The evidence for this variant shows missense in EZH2, where missense can be pathogenic. Therefore, this criterion is not applied because the gene does not only tolerate LoF variants.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'BP2 – Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. The evidence for this variant shows no such observations. Therefore, this criterion is not applied due to lack of phase information.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'BP3 – In-frame deletions/insertions in a repetitive region without known function'. The evidence for this variant shows a single amino acid substitution, not an indel. Therefore, this criterion is not applied because it does not meet the variant type.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: 'BP4 – Multiple lines of computational evidence suggest no impact'. The evidence for this variant shows damaging predictions from multiple tools. Therefore, this criterion is not applied because computational evidence indicates deleterious effect.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'BP5 – Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows no such case data. Therefore, this criterion is not applied due to lack of case context.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'BP6 – Reputable source reports variant as benign, but without accessible evidence'. The evidence for this variant shows no benign assertions. Therefore, this criterion is not applied because no reputable benign report exists.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'BP7 – Synonymous variant with no predicted impact on splicing'. The evidence for this variant shows a missense change, not synonymous. Therefore, this criterion is not applied because the variant is not synonymous.