NM_004456.4:c.1851G>A

EZH2 · NP_004447.2:p.(Lys617=) · NM_004456.4

GRCh37: chr7:148511051 C>T · GRCh38: chr7:148813959 C>T

Gene: EZH2 Transcript: NM_004456.4

Final call

VUS

PM2 supporting BP7 supporting

Variant details

Gene

EZH2

Transcript

NM_004456.4

Protein

NP_004447.2:p.(Lys617=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This 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.	spliceai pvs1_generic_framework
PS1	Not met	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.
PS2	Not met	No de novo occurrence data with confirmed maternity and paternity was identified for this variant in any evidence source.
PS3	Not met	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.
PS4	Not met	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.
PS5	Not met	No established functional assay demonstrating a damaging effect for this variant was identified. No publications or curated functional data are available.
PM1	Not met	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.
PM2	Met	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%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	This 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.
PM6	Not met	No de novo occurrence was identified for this variant in any evidence source. No publications report this variant as a de novo event.
PP1	Not met	No co-segregation data is available for this variant. No family studies or pedigrees were identified in the evidence sources.
PP2	N/A	PP2 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.
PP3	Not met	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.	spliceai
PP4	Not met	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.
PP5	Not met	This variant is absent from ClinVar. No reputable source, including expert panels, has classified this variant as pathogenic.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the BA1 threshold (allele frequency >1%).	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the BS1 threshold (allele frequency >0.3%).	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	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.
BS3	Not met	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.
BS4	Not met	No segregation data is available to evaluate non-segregation with disease.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. This variant is synonymous (p.Lys617=), not a missense change.
BP2	Not met	No data on observation of this variant in trans with a pathogenic variant in a fully penetrant dominant disorder is available.
BP4	Not met	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.	spliceai
BP5	Not met	No case with an alternate molecular basis for disease was identified.
BP6	Not met	This variant is absent from ClinVar. No reputable source has classified this variant as benign.	clinvar
BP7	Met	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.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.