The EZH2 c.1797G>A (p.Trp599Ter; p.W599*) variant has been reported in ClinVar as a variant of uncertain significance with one clinical laboratory submission.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the usual PM2 population threshold of 0.1% for a rare germline disorder.2 This nonsense variant is predicted to introduce a premature termination codon in exon 15 with downstream coding exons remaining, and generic PVS1 review indicates that EZH2 is eligible for loss-of-function assessment under the ClinGen SVI framework.3 SpliceAI predicts no significant splice impact for this variant (maximum delta score 0.01), while BayesDel is 0.655873; these computational findings do not provide standalone benign support for this truncating variant.4
Final classification
Likely Pathogenic
PVS1PM2
EZH2
c.1797G>A
p.Trp599Ter
This variant
The EZH2 c.1797G>A (p.Trp599Ter; p.W599*) variant has been reported in ClinVar as a variant of uncertain significance with one clinical laboratory submission.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 supporting; combination = 1 very strong + 1 supporting, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
EZH2 c.1797G>A
PVS1 + PM2
→
Likely Pathogenic
3
pvs1_variant_assessmentpvs1_gene_contextpvs1_generic_framework ↗
4
spliceai ↗bayesdel
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.
Gene diagram
· NM_004456.4 · variants mapped to exon structure
EZH2
NM_004456.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
PVS1
very strong
review
Pathogenic
This variant is a nonsense change, p.Trp599Ter, in exon 15 and is followed by multiple downstream coding exons, which is consistent with a premature termination codon expected to trigger nonsense-mediated decay. EZH2 was flagged as eligible for generic loss-of-function assessment, so PVS1 is met under the ClinGen SVI generic PVS1 framework, although human review remains appropriate because no gene-specific specification was available.
Nonsense variant p.Trp599TerVariant maps to exon 15 with downstream coding exons remainingGeneric PVS1 eligibility for EZH2 loss-of-function review
PM2
supporting
review
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the usual PM2 rarity threshold of 0.1% for a rare germline disorder. These population data support PM2 at supporting strength.
Absent from gnomAD v2.1Absent from gnomAD v4.1
Assessed · not applied
· 7 not met · 11 not assessed
Pathogenic
PS1
No evidence was identified for a different pathogenic nucleotide change that results in the same p.Trp599Ter protein effect, so PS1 was not assessed.
PS2
No confirmed de novo occurrence with maternity and paternity established was identified for this variant, so PS2 was not assessed.
PS3
Published studies reviewed describe EZH2 loss-of-function biology at the gene level, including somatic mutations and EZH2 deletion models, but they do not provide a well-established functional assay directly testing p.Trp599Ter.
PS4
This variant has one ClinVar submission and no case-control or recurrence data demonstrating enrichment in affected individuals.
PM1
This variant has not been shown to lie in a well-established mutational hotspot or critical domain without benign variation.
PM3
No evidence was identified for this variant in trans with another pathogenic variant in an established recessive disease context, so PM3 was not assessed.
PM6
No presumed de novo report without confirmed parentage was identified for this variant, so PM6 was not assessed.
PP1
No segregation data were identified for this variant, so PP1 was not assessed.
PP3
SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.01, and BayesDel is 0.655873; no REVEL score was available.
PP4
No patient-specific phenotype information was provided that could be assessed for high specificity to an EZH2-related disorder, so PP4 was not assessed.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is far below the 1% BA1 threshold.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the usual BS1 threshold of 0.3%.
BS2
No evidence was identified showing this variant in healthy adults under circumstances sufficient to argue against pathogenicity, so BS2 was not assessed.
BS3
Published studies reviewed address EZH2 loss-of-function at the gene level, but no well-established functional study was identified showing normal function for p.Trp599Ter.
BS4
No non-segregation data were identified for this variant, so BS4 was not assessed.
BP2
No evidence was identified that this variant is observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant in a way that supports BP2, so BP2 was not assessed.
BP4
SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, but BayesDel is 0.655873 and does not support a benign interpretation; no REVEL score was available.
BP5
No alternate molecular explanation for the relevant phenotype was provided, so BP5 was not assessed.
N/A · 8
PM4 · PM5 · PP2 · PP5 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.655873.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links