EZH2 c.1871C>T, p.Ser624Phe
NM_004456.4:c.1871C>T
Variant of Uncertain Significance (VUS)
EZH2 c.1871C>T (p.S624F) is absent from population databases (PM2) and predicted deleterious by multiple in silico tools (PP3), but lacks functional, segregation, de novo or case data. Therefore, it remains classified as a Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
PP3
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.1871C>T
Protein Change
S624F
Location
Exon 16
(Exon 16 of 20)
5'Exon Structure (20 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 624 in gene EZH2
Variant interpretation based on transcript NM_004456.5
Genome Browser
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HGVS InputNM_004456:c.1871C>T
Active Tracks
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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 624 in gene EZH2
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.94
0.94
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: 6.07
Neutral: Show all
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 (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon or multi-exon deletion) in a gene where loss of function is a known mechanism of disease.' The evidence for this variant shows: it is a missense change (S624F), not a null variant. Therefore, this criterion is not applied at strength Not Applied because the variant type does not meet the definition of a null variant.
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 other pathogenic variant at amino acid position 624 in EZH2 has been reported. Therefore, this criterion is not applied at strength Not Applied because there is no known 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 information on de novo occurrence or parental testing. Therefore, this criterion is not applied at strength Not Applied because de novo status has not been evaluated.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.' The evidence for this variant shows: no functional studies have been performed for EZH2 S624F. Therefore, this criterion is not applied at strength Not Applied because functional impact has not been assessed.
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 data or disease cohort enrichment reported. Therefore, this criterion is not applied at strength Not Applied because there is no prevalence data.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot and/or well-established functional domain without benign variation.' The evidence for this variant shows: no information on a mutational hot spot or critical domain at residue 624. Therefore, this criterion is not applied at strength Not Applied because domain context is not established.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive) in population databases.' The evidence for this variant shows: not present in gnomAD or other population databases. Therefore, this criterion is applied at strength Moderate because the variant is absent from 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 a recessive disorder.' The evidence for this variant shows: EZH2-associated disorder is dominant and no trans data are available. Therefore, this criterion is not applied at strength Not Applied because trans configuration is not relevant or reported.
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: it is a missense substitution with no change in protein length. Therefore, this criterion is not applied at strength Not Applied because there is no protein length alteration.
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 variants reported at residue S624. Therefore, this criterion is not applied at strength Not Applied because no prior pathogenic missense at this residue is known.
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 information on parental testing or assumed de novo status. Therefore, this criterion is not applied at strength Not Applied because de novo assumption is not supported.
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 segregation data available. Therefore, this criterion is not applied at strength Not Applied because family segregation has not been assessed.
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 gene-specific data on benign missense rate. Therefore, this criterion is not applied at strength Not Applied because gene-specific missense constraint is not established.
PP3
PP3 (Supporting)
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product.' The evidence for this variant shows: REVEL score of 0.94 (>0.75) and multiple in silico tools predict deleterious effect. Therefore, this criterion is applied at strength Supporting because computational evidence supports a damaging effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: no phenotype or clinical information provided. Therefore, this criterion is not applied at strength Not Applied because phenotype specificity is not 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: not present in ClinVar or other curated sources. Therefore, this criterion is not applied at strength Not Applied because no reputable pathogenic assertion exists.
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 strength Not Applied because frequency is not above threshold.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for disorder.' The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied at strength Not Applied because frequency is not elevated.
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 expected full penetrance.' The evidence for this variant shows: no observations in healthy adult carriers. Therefore, this criterion is not applied at strength Not Applied because carrier status in healthy individuals is unknown.
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 studies available. Therefore, this criterion is not applied at strength Not Applied because functional neutrality has not been demonstrated.
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 family data provided. Therefore, this criterion is not applied at strength Not Applied because segregation data are 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: EZH2 missense variants are known to cause disease. Therefore, this criterion is not applied at strength Not Applied because missense is a recognized pathogenic 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 a dominant disorder or in cis with another pathogenic variant.' The evidence for this variant shows: no information on cis/trans configuration with other variants. Therefore, this criterion is not applied at strength Not Applied because phase information is not available.
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 substitution, not an in-frame indel. Therefore, this criterion is not applied at strength Not Applied because 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 or gene product.' The evidence for this variant shows: computational tools predict deleterious effect. Therefore, this criterion is not applied at strength Not Applied because in silico evidence is not benign.
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 cases reported with alternative molecular diagnoses. Therefore, this criterion is not applied at strength Not Applied because no such case context exists.
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 benign assertions in databases. Therefore, this criterion is not applied at strength Not Applied because no reputable benign report is available.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no impact on splicing.' The evidence for this variant shows: it is a missense variant, not synonymous. Therefore, this criterion is not applied at strength Not Applied because it is not a synonymous change.