EZH2 c.259A>T, p.Ser87Cys
NM_004456.4:c.259A>T
Variant of Uncertain Significance (VUS)
The variant NM_004456.4:c.259A>T (p.S87C) in EZH2 is absent from population databases (PM2 Moderate) and lacks sufficient additional evidence for or against pathogenicity. No functional, segregation, de novo, computational, or clinical specificity data are available. Based on ACMG criteria, it remains a Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
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.259A>T
Protein Change
S87C
Location
Exon 4
(Exon 4 of 20)
5'Exon Structure (20 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 87 in gene EZH2
Variant interpretation based on transcript NM_004456.5
Genome Browser
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HGVS InputNM_004456:c.259A>T
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 87 in gene EZH2
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
SpliceAI Scores Window: ±500bp
| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss | 0.0 | -2 bp |
| Donor Loss | 0.0 | 417 bp |
| Acceptor Gain | 0.0 | 38 bp |
| Donor Gain | 0.0 | -70 bp |
High impact (≥0.5)
Medium impact (0.2-0.49)
Low impact (<0.2)
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease". The evidence for this variant shows: it is a missense change (S87C), not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant does not result in a null allele.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change". The evidence for this variant shows: no known pathogenic variant results in S87C. Therefore, this criterion is not applied at Not Applied strength because there is no established pathogenic variant with the same amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no de novo or inheritance data are available. Therefore, this criterion is not applied at Not Applied strength because de novo status cannot be assessed without confirmed parental testing.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: no functional characterization has been performed for S87C. Therefore, this criterion is not applied at Not Applied strength because functional data are not available.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case-control or cohort data are available. Therefore, this criterion is not applied at Not Applied strength because there is no evidence of enrichment in affected individuals.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: S87 is not within a recognized mutational hotspot or critical functional domain of EZH2. Therefore, this criterion is not applied at Not Applied strength because the variant does not fall in a known hotspot or domain.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium". The evidence for this variant shows: it is not present in gnomAD or other population databases (MAF=0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for recessive disorders". The evidence for this variant shows: EZH2-related disease is autosomal dominant and no trans data are relevant. Therefore, this criterion is not applied at Not Applied strength because the gene is not recessive and no trans-phase data apply.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: S87C is a missense change without change in protein length. Therefore, this criterion is not applied at Not Applied strength because there is no alteration in protein length.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "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 missense changes have been reported at residue S87. Therefore, this criterion is not applied at Not Applied strength because there is no prior pathogenic missense at this residue.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no inheritance data are available. Therefore, this criterion is not applied at Not Applied strength because de novo status has not been assessed.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no family segregation data are available. Therefore, this criterion is not applied at Not Applied strength because segregation data are lacking.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "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 shows: insufficient data on benign missense variation rate and mechanism for EZH2. Therefore, this criterion is not applied at Not Applied strength because evidence for the gene's missense constraint is not provided.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product". The evidence for this variant shows: no in silico predictions or conservation analyses are available. Therefore, this criterion is not applied at Not Applied strength because computational evidence is missing.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no clinical phenotype or family history data are provided. Therefore, this criterion is not applied at Not Applied strength because phenotype specificity cannot be evaluated.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: no entries in ClinVar or other databases. Therefore, this criterion is not applied at Not Applied strength because no reputable source reports this variant as pathogenic.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder". The evidence for this variant shows: allele frequency is 0% in population databases. Therefore, this criterion is not applied at Not Applied strength because the variant is not common.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder". The evidence for this variant shows: allele frequency is absent. Therefore, this criterion is not applied at Not Applied strength because frequency does not exceed expectation.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age". The evidence for this variant shows: no data on healthy adult carriers. Therefore, this criterion is not applied at Not Applied strength because carrier phenotype data are unavailable.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: no functional assays. Therefore, this criterion is not applied at Not Applied strength because functional studies are lacking.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no segregation studies. Therefore, this criterion is not applied at Not Applied strength because segregation analysis is not available.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only loss-of-function causes disease". The evidence for this variant shows: missense variants in EZH2 are known to cause disease. Therefore, this criterion is not applied at Not Applied strength because missense is an established mechanism.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no phase data. Therefore, this criterion is not applied at Not Applied strength because cis/trans information is unavailable.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: it is a missense change, not an in-frame indel. Therefore, this criterion is not applied at Not Applied strength because the variant type does not match.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene/gene product". The evidence for this variant shows: no computational evidence. Therefore, this criterion is not applied at Not Applied strength because in silico data are missing.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no case reports. Therefore, this criterion is not applied at Not Applied strength because no alternate molecular basis is documented.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: no database entries. Therefore, this criterion is not applied at Not Applied strength because no reputable source reports it as benign.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: it is a missense change, not synonymous. Therefore, this criterion is not applied at Not Applied strength because the variant is not synonymous.