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EZH2c.1851G>AUncertain significance
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Variant interpretation report

EZH2 c.1851G>A, p.(Lys617=)

NM_004456.4:c.1851G>A NP_004447.2:p.(Lys617=) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About EZH2

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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%).

Benign criteria applied · 1
BP7Supporting
BP7 · supporting

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.

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP7 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 2 met · 20 not met · 0 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

SpliceAI predicts no splicing impact (max delta score 0.00), consistent with a silent synonymous change. This satisfies BP7 at supporting strength.

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.

Met · 2

PM2 SupportingThis 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%). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
  • Absent from gnomAD-Canada v1.0
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP7 SupportingThis 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. Details ▾Hide ▴
Evidence considered
  • Synonymous variant p.(Lys617=)
  • SpliceAI max delta 0.00 — no splice impact predicted
  • No cryptic splice site creation or disruption
Still missing
  • Nucleotide conservation data (phyloP/GERP) not available to confirm non-conserved status
Sources
spliceai ↗

Not met · 20 · evaluated, threshold not reached

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. No pathogenic missense comparator at this codon exists to satisfy PS1. Details ▾Hide ▴
Evidence considered
  • Synonymous variant p.(Lys617=) — no amino acid change
PS2 No de novo occurrence data with confirmed maternity and paternity was identified for this variant in any evidence source. Details ▾Hide ▴
Still missing
  • No de novo testing data available
PS3 No functional studies testing this variant or a systematically characterized range encompassing this position were identified in the literature or curated databases. No publications were retrieved for this variant. Details ▾Hide ▴
Still missing
  • No functional data available for NM_004456.4:c.1851G>A
PS4 No case-control or cohort data demonstrating enrichment of this variant in affected individuals versus controls was identified. The variant is absent from ClinVar and COSMIC. Details ▾Hide ▴
Still missing
  • No case-control or prevalence data available
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. Cancerhotspots.org does not identify this residue as a statistically significant hotspot. The variant does not alter the protein sequence, so PM1 at the domain level does not apply. Details ▾Hide ▴
Evidence considered
  • Synonymous variant — no amino acid change
  • Not a cancerhotspots.org significant hotspot
  • SpliceAI max delta 0.00 — no cryptic splice site creation
PM6 No de novo occurrence was identified for this variant in any evidence source. No publications report this variant as a de novo event. Details ▾Hide ▴
Still missing
  • No de novo data available
PP1 No co-segregation data is available for this variant. No family studies or pedigrees were identified in the evidence sources. Details ▾Hide ▴
Still missing
  • No segregation data available
PP3 In silico predictors do not support a deleterious effect. SpliceAI predicts no splicing impact (max delta 0.00). REVEL and BayesDel scores are not available for this synonymous variant. No computational evidence supports pathogenicity. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.00 — no splice impact
  • REVEL not computed for synonymous variant
  • BayesDel not found
Sources
spliceai ↗
PP4 No patient phenotype or family history data is available. PP4 requires that the patient's phenotype or family history is highly specific for the disease with a single genetic etiology. Details ▾Hide ▴
Still missing
  • No phenotypic data available
PP5 This variant is absent from ClinVar. No reputable source, including expert panels, has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar — no pathogenic classifications
Sources
clinvar ↗
BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the BA1 threshold (allele frequency >1%). Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD datasets — 0% allele frequency
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the BS1 threshold (allele frequency >0.3%). Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD datasets — 0% allele frequency
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 No data on observation of this variant in healthy adults is available. BS2 requires observation in healthy adult individuals with full penetrance expected at an early age. Details ▾Hide ▴
Still missing
  • No healthy control data available
BS3 No functional studies demonstrating no damaging effect for this variant were identified. SpliceAI predicts no splicing impact, but this constitutes in silico evidence (BP4/BP7 territory), not functional evidence for BS3. Details ▾Hide ▴
Evidence considered
  • No functional data available
Still missing
  • No functional studies testing this variant
BS4 No segregation data is available to evaluate non-segregation with disease. Details ▾Hide ▴
Still missing
  • No segregation data available
BP2 No data on observation of this variant in trans with a pathogenic variant in a fully penetrant dominant disorder is available. Details ▾Hide ▴
Still missing
  • No trans configuration data available
BP4 BP4 requires multiple lines of computational evidence suggesting no impact. Only SpliceAI data is available (max delta 0.00). REVEL and BayesDel scores are not available for this synonymous variant. A single line of computational evidence is insufficient to meet BP4. SpliceAI data is applied under BP7 instead. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.00 — single computational line
  • Insufficient for 'multiple lines' requirement of BP4
Still missing
  • No REVEL
  • BayesDel
  • or conservation scores available
Sources
spliceai ↗
BP5 No case with an alternate molecular basis for disease was identified. Details ▾Hide ▴
Still missing
  • No alternate molecular basis data available
BP6 This variant is absent from ClinVar. No reputable source has classified this variant as benign. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar — no benign classifications
Sources
clinvar ↗
PS5 No established functional assay demonstrating a damaging effect for this variant was identified. No publications or curated functional data are available. Details ▾Hide ▴
Still missing
  • No functional assay data available
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is synonymous (NP_004447.2:p.(Lys617=)) and does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. SpliceAI predicts no splice impact (max delta 0.00). PVS1 is not applicable to a synonymous variant without predicted splicing disruption. Details ▾Hide ▴
Evidence considered
  • Synonymous variant p.(Lys617=)
  • no protein truncation
  • SpliceAI max delta 0.00 — no splice impact predicted
  • Variant does not meet any PVS1 null-variant bucket per PMC6185798
Sources
spliceai ↗pvs1_generic_framework ↗
PM5 N/AThis is a synonymous variant (p.Lys617=) producing no amino acid change. PM5 requires a different missense change at the same codon classified as pathogenic. A synonymous variant does not produce a missense change, so PM5 is not applicable. Details ▾Hide ▴
Evidence considered
  • Synonymous variant — no amino acid change to compare
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation and where missense is a common disease mechanism. This variant is synonymous (p.Lys617=), not a missense change. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • not missense
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. This variant is synonymous (p.Lys617=), not a missense change. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • not missense

Identifiers

Gene
EZH2
Transcript
NM_004456.4
Coding (HGVS c.)
NM_004456.4:c.1851G>A
Protein (HGVS p.)
NP_004447.2:p.(Lys617=)
GRCh38
chr7:148813959 C>T
GRCh37
chr7:148511051 C>T

Gene diagram

Every interpreted variant in EZH2, mapped onto the exon structure of NM_004456.4. Select a row to find it on the plot.

EZH2NM_004456.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.230
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP7 SupportingThis 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. Details ▾Hide ▴
Evidence considered
  • Synonymous variant p.(Lys617=)
  • SpliceAI max delta 0.00 — no splice impact predicted
  • No cryptic splice site creation or disruption
Still missing
  • Nucleotide conservation data (phyloP/GERP) not available to confirm non-conserved status
Sources
spliceai ↗
PP3 In silico predictors do not support a deleterious effect. SpliceAI predicts no splicing impact (max delta 0.00). REVEL and BayesDel scores are not available for this synonymous variant. No computational evidence supports pathogenicity. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.00 — no splice impact
  • REVEL not computed for synonymous variant
  • BayesDel not found
Sources
spliceai ↗
BP4 BP4 requires multiple lines of computational evidence suggesting no impact. Only SpliceAI data is available (max delta 0.00). REVEL and BayesDel scores are not available for this synonymous variant. A single line of computational evidence is insufficient to meet BP4. SpliceAI data is applied under BP7 instead. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.00 — single computational line
  • Insufficient for 'multiple lines' requirement of BP4
Still missing
  • No REVEL
  • BayesDel
  • or conservation scores available
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.