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LYFE SCIENCES
Project: HERA
NM_004456.4:c.1797G>A
p.Trp599Ter  ·  EZH2
ACMG/AMP
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗
3

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.

pvs1_generic_framework ↗
4

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.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.655873.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueW599
Hotspots ↗