NM_004456.4:c.1797G>A

EZH2 · NP_004447.2:p.(Trp599Ter) · NM_004456.4

GRCh37: chr7:148511105 C>T · GRCh38: chr7:148814013 C>T

Gene: EZH2 Transcript: NM_004456.4

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

EZH2

Transcript

NM_004456.4

Protein

NP_004447.2:p.(Trp599Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	Met	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.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified for a different pathogenic nucleotide change that results in the same p.Trp599Ter protein effect, so PS1 was not assessed.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity established was identified for this variant, so PS2 was not assessed.	clinvar
PS3	Not met	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. Available evidence therefore does not support PS3 for this specific variant.	PMID:20601954 PMID:27926872 oncokb
PS4	Not met	This variant has one ClinVar submission and no case-control or recurrence data demonstrating enrichment in affected individuals. Available evidence does not support a statistically increased prevalence in affected individuals, so PS4 is not met.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	This variant has not been shown to lie in a well-established mutational hotspot or critical domain without benign variation. Available hotspot review does not support PM1.	hotspots
PM2	Met	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.	gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified for this variant in trans with another pathogenic variant in an established recessive disease context, so PM3 was not assessed.	clinvar
PM4	N/A	PM4 addresses protein length changes from in-frame insertions, deletions, or stop-loss variants. This variant is a nonsense change, so PM4 is not applicable.	pvs1_variant_assessment
PM5	N/A	PM5 applies to a novel missense change at an amino acid residue where a different pathogenic missense change has been seen. This variant is a nonsense change, so PM5 is not applicable.	pvs1_variant_assessment
PM6	Not assessed	No presumed de novo report without confirmed parentage was identified for this variant, so PM6 was not assessed.	clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not assessed.	clinvar
PP2	N/A	PP2 is used for missense variants in genes where missense variation is a common disease mechanism and benign missense variation is rare. This variant is a nonsense change, so PP2 is not applicable.	pvs1_variant_assessment
PP3	Not assessed	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. These computational findings were reviewed, but PP3 was not applied because this is a clear nonsense variant already addressed through PVS1 rather than a missense or splice-prediction driven interpretation.	spliceai bayesdel
PP4	Not assessed	No patient-specific phenotype information was provided that could be assessed for high specificity to an EZH2-related disorder, so PP4 was not assessed.	clinvar
PP5	N/A	PP5 was not applied. The only ClinVar assertion identified was a single-submitter variant of uncertain significance, and classification was not based on an external assertion alone.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is far below the 1% BA1 threshold. BA1 is not met.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the usual BS1 threshold of 0.3%. BS1 is not met.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adults under circumstances sufficient to argue against pathogenicity, so BS2 was not assessed.	gnomad_v2 gnomad_v4
BS3	Not met	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. Available evidence does not support BS3 for this variant.	PMID:20601954 PMID:27926872 oncokb
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 was not assessed.	clinvar
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the predominant disease mechanism. This variant is a nonsense change, so BP1 is not applicable.	pvs1_variant_assessment
BP2	Not assessed	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.	clinvar
BP3	N/A	BP3 addresses in-frame insertions or deletions in repetitive regions without known function. This variant is a nonsense substitution, so BP3 is not applicable.	pvs1_variant_assessment
BP4	Not met	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. Overall, computational evidence does not support a benign effect, so BP4 is not met.	spliceai bayesdel
BP5	Not assessed	No alternate molecular explanation for the relevant phenotype was provided, so BP5 was not assessed.	clinvar
BP6	N/A	BP6 was not applied. No benign or likely benign assertion from a source used without accessible evidence was identified, and the available ClinVar submission is a variant of uncertain significance.	clinvar
BP7	N/A	BP7 applies to synonymous or certain intronic variants with no predicted splice impact. This variant is a nonsense coding change, so BP7 is not applicable.	spliceai pvs1_variant_assessment

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