NM_004456.4:c.1851G>A is a synonymous variant (p.Lys617=) in exon 15 of EZH2, encoding a residue within the SET domain. This variant is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.1 SpliceAI predicts no splicing impact (max delta score 0.00), consistent with a silent synonymous change. This satisfies BP7 at supporting strength.2 No functional studies, case-control data, segregation data, or literature reports were identified for this variant. It is absent from ClinVar and COSMIC. With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP7), the evidence is equivocal. The variant is classified as a Variant of Uncertain Significance (VUS) per generic ACMG/AMP 2015 classification rules.3
EZH2
Final classification
VUS
EZH2 c.1851G>A · p.Lys617=
EZH2
NM_004456.4:c.1851G>A is a synonymous variant (p.Lys617=) in exon 15 of EZH2, encoding a residue within the SET domain.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP7 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP7
VUS
EZH2 c.1851G>A
PM2 + BP7
→
VUS
Gene diagram
· NM_004456.4 · variants mapped to exon structure
EZH2
NM_004456.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Meets PM2 threshold for absence from population databases (allele frequency <0.1%).
Absent from gnomAD v2.1Absent from gnomAD v4.1Absent from gnomAD-Canada v1.0
✓
BP7
supporting
review
Benign
This is a synonymous variant (p.Lys617=) with no predicted splice impact. SpliceAI predicts no splicing alteration (max delta score 0.00, no acceptor gain/loss, no donor gain/loss). Meets BP7 at supporting strength. Nucleotide-level conservation data (phyloP/GERP) is not available; human review recommended to confirm the nucleotide is not highly conserved.
Synonymous variant p.(Lys617=)SpliceAI max delta 0.00 — no splice impact predictedNo cryptic splice site creation or disruption
Assessed · not applied
Pathogenic
PS1
This is a synonymous variant with no amino acid change; it cannot represent the same amino acid change as a previously established pathogenic variant.
PS2
No de novo occurrence data with confirmed maternity and paternity was identified for this variant in any evidence source.
PS3
No functional studies testing this variant or a systematically characterized range encompassing this position were identified in the literature or curated databases.
PS4
No case-control or cohort data demonstrating enrichment of this variant in affected individuals versus controls was identified.
PM1
Although the variant lies within the SET domain of EZH2 (exon 15), this is a synonymous variant (p.Lys617=) with no predicted splice impact.
PM6
No de novo occurrence was identified for this variant in any evidence source.
PP1
No co-segregation data is available for this variant.
PP3
In silico predictors do not support a deleterious effect.
PP4
No patient phenotype or family history data is available.
PP5
This variant is absent from ClinVar.
Benign
BA1
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS2
No data on observation of this variant in healthy adults is available.
BS3
No functional studies demonstrating no damaging effect for this variant were identified.
BS4
No segregation data is available to evaluate non-segregation with disease.
BP2
No data on observation of this variant in trans with a pathogenic variant in a fully penetrant dominant disorder is available.
BP4
BP4 requires multiple lines of computational evidence suggesting no impact.
BP5
No case with an alternate molecular basis for disease was identified.
BP6
This variant is absent from ClinVar.
N/A · 4
PVS1 · PM5 · PP2 · BP1
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
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.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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