EZH2 c.553G>C, p.Asp185His
NM_004456.4:c.553G>C
COSMIC ID: COSM3762469
Likely Benign
This EZH2 D185H variant has a very high population frequency (MAF 7.65% with homozygotes) meeting BA1 and is observed in healthy individuals (BS2). Computational predictions and ClinVar support benign impact (BP4, BP6). No pathogenic evidence is present. These data fulfill stand-alone and strong benign criteria, leading to a final classification of Benign.
ACMG/AMP Criteria Applied
BA1
BS1
BS2
BP4
BP6
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.553G>C
Protein Change
D185H
Location
Exon 6
(Exon 6 of 20)
5'Exon Structure (20 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 185 in gene EZH2
Alternate Identifiers
COSM3762469
Variant interpretation based on transcript NM_004456.5
Genome Browser
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HGVS InputNM_004456:c.553G>C
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Clinical Data
Global Frequency
7.65%
Common
Highest in Population
East Asian
17.7%
Common
Global: 7.65%
East Asian: 17.7%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 279706Alt: 21406Homozygotes: 1062
ACMG Criteria Applied
BA1
This variant is present in gnomAD (MAF= 7.65%, 21406/279706 alleles, homozygotes = 1062) and at a higher frequency in the East Asian population (MAF= 17.7%, 3508/19830 alleles, homozygotes = 326). The variant is common (MAF > 1%), supporting BA1 criterion application.
Classification
Benign
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
5 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Benign (5 clinical laboratories).
COSMIC ID
COSM3762469
Recurrence
78 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
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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 185 in gene EZH2
Functional Summary
The EZH2 D185H variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.454
0.454
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
No
Additional Predictors
Benign:
CADD: 5.47metasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PVS1 is for null variants in a gene where loss of function is a known disease mechanism. The evidence for this variant shows it is a missense change (D185H) with no predicted null effect. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS1 is for the same amino acid change as a known pathogenic variant via a different nucleotide change. There is no known pathogenic D185H in EZH2 reported. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 requires confirmed de novo occurrence. No parental testing data are available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS3 requires well-established functional studies supportive of a damaging effect. No functional studies have been performed for D185H. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 requires increased prevalence in affected individuals compared to controls. No case-control or affected individual data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 is for variants in mutational hotspots or well-established functional domains. D185 is not documented as a hotspot or critical domain residue. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM2 requires absence or extremely low frequency in controls. The variant has a MAF of 7.65% in gnomAD with 1,062 homozygotes. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies to recessive disorders when detected in trans with a pathogenic variant. No trans data are available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 is for protein length changes due to in-frame indels or stop‐loss variants. D185H is a missense change with no length alteration. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM5 is for novel missense changes at residues with other known pathogenic missense variants. No other pathogenic change at D185 is reported. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo cases without confirmation. No de novo assumption data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1 requires co-segregation with disease in multiple affected family members. No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low benign variation and where missense is a common disease mechanism. EZH2 has known pathogenic missense variants but also common benign variation. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP3 requires multiple lines of computational evidence supporting deleterious effect. In silico predictors are predominantly benign and SpliceAI predicts no splicing impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 is for a highly specific patient phenotype. No phenotype data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 requires a reputable source reporting pathogenicity. ClinVar reports this variant as benign. Therefore, this criterion is not applied.
BA1
BA1 (Stand Alone) Strength Modified
According to standard ACMG guidelines, BA1 is: 'Allele frequency is too high for the disorder (based on population data)'. The evidence for this variant shows a MAF of 7.65% in gnomAD with 1,062 homozygotes. Therefore, this criterion is applied at Stand Alone strength because allele frequency far exceeds any threshold for pathogenicity.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS1 is: 'Allele frequency is greater than expected for the disorder'. BA1 already covers the stand-alone frequency rule; BS1 is not separately applied to avoid double counting.
BS2
BS2 (Strong)
According to standard ACMG guidelines, BS2 is: 'Observed in healthy individuals with full penetrance expected at an early age'. The evidence for this variant shows multiple homozygotes in gnomAD, indicating presence in healthy individuals. Therefore, this criterion is applied at Strong strength.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS3 requires well-established functional studies showing no damaging effect. No such functional studies exist for D185H. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 requires lack of segregation in affected family members. No family segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in a gene where only loss-of-function causes disease. EZH2 pathogenic mechanism includes gain-of-function missense variants. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when a variant is observed in trans with a pathogenic variant for a dominant disorder. No such observations are reported. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This is a missense variant. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product'. In silico tools (CADD, MetaSVM, MetaLR, PrimateAI, REVEL=0.45) and SpliceAI predict no impact. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when a variant is found in a case with an alternate molecular basis for disease. No such case data are provided. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. ClinVar lists this variant as Benign from five clinical labs. Therefore, this criterion is applied at Supporting strength.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP7 applies to synonymous variants with no splicing impact. This is a missense variant. Therefore, this criterion is not applied.