Variant classification summary

NM_004364.3:c.926_928dupAGA

CEBPA · NP_004355.2:p.(Glu309_Thr310insLys) · NM_004364.3

GRCh37: chr19:33792392 G>GTCT · GRCh38: chr19:33301486 G>GTCT

Gene: CEBPA Transcript: NM_004364.3

Final call

Likely Pathogenic

PM1 moderate PM2 moderate PM4 moderate

Variant details

Gene

CEBPA

Transcript

NM_004364.3

Protein

NP_004355.2:p.(Glu309_Thr310insLys)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM1 (moderate): The variant lies within the CEBPA bZIP domain (codons ~278-358), a well-established critical functional domain where pathogenic mutations cluster. No benign variation is observed in this region.

2

PM2 (moderate): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0.0), meeting the <0.1% threshold for moderate evidence of rarity.

3

PM4 (moderate): The variant is an in-frame duplication (p.Glu309_Thr310insLys) causing protein length change in a non-repeat region, consistent with a disease-causing mechanism.

4

Three moderate criteria (PM1, PM2, PM4) are met with no benign criteria met. Per ACMG/AMP 2015 combination rules (PMID:25741868), ≥3 moderate criteria support classification as Likely Pathogenic.

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	N/A	NM_004364.3:c.926_928dup is an in-frame duplication (p.Glu309_Thr310insLys), not a null variant (nonsense, frameshift, or canonical splice). Per ClinGen SVI PVS1 recommendations (PMC6185798), PVS1 does not apply to in-frame insertions.	pvs1_generic_framework
PS1	N/A	PS1 requires a different nucleotide change leading to the same amino acid change that has been previously classified as pathogenic. No such comparator pathogenic variant exists for p.Glu309_Thr310insLys.
PS2	Not assessed	No de novo observation data are available for this variant in any database or publication reviewed.
PS3	Not assessed	No variant-specific functional studies were identified. Five publications (PMID:11830484, 33951732, 34320176, 34448807, 38228680) discuss CEBPA mutations at the gene level in AML prognosis but do not report functional characterization of NM_004364.3:c.926_928dupAGA. Full-text search of available papers confirmed the variant is not mentioned.
PS4	Not assessed	The variant is absent from ClinVar and absent from gnomAD; no case-control data are available to evaluate whether prevalence is significantly increased in affected individuals versus controls. COSMIC somatic occurrence (COSV57195593, n=9) does not inform germline PS4.	gnomad_v2 gnomad_v4 clinvar
PS5	Not assessed	No reputable germline diagnostic source has reported this variant as pathogenic with supporting evidence suitable for PS5. OncoKB classifies this variant as 'Likely Oncogenic' in a somatic context, which does not constitute a germline pathogenicity assertion.	oncokb
PM1	Met	The variant is located at codon 309-310 within the CEBPA bZIP domain (approximately codons 278-358), a well-established critical functional domain required for DNA binding and dimerization. Pathogenic CEBPA mutations cluster in the bZIP domain, and no benign variants are reported in this region.	gnomad_v2 gnomad_v4
PM2	Met	The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele frequency = 0.0), meeting the <0.1% threshold for PM2 in the absence of a gene-specific CSPEC framework.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	Met	The variant is an in-frame duplication (c.926_928dup) resulting in insertion of a lysine residue (p.Glu309_Thr310insLys), causing protein length change in a non-repeat region. This meets the PM4 criterion for in-frame insertions in a non-repeat region.
PM5	N/A	PM5 applies to missense variants at a residue where a different missense change has been classified as pathogenic. This variant is an in-frame insertion (p.Glu309_Thr310insLys), not a missense change. The automated PM5 candidate search confirmed this is not applicable.	pm5_candidates
PM6	Not assessed	No de novo observation data are available for this variant. PM6 requires confirmed de novo occurrence with parental testing.
PP1	Not assessed	No cosegregation data are available for this variant in any family.
PP2	N/A	PP2 applies specifically to missense variants in genes with a low rate of benign missense variation. This variant is an in-frame duplication, not a missense variant.
PP3	Not met	Multiple lines of computational evidence supporting pathogenicity are not available. REVEL and BayesDel are not applicable to indels. SpliceAI predicts no splice impact (max delta score = 0.01). No HCI prior probability score is available for CEBPA. Insufficient computational evidence to support PP3.	spliceai
PP4	Not assessed	No patient-specific phenotype or family history data are available for this variant. PP4 requires the patient's phenotype or family history to be highly specific for the disease.
PP5	Not met	No germline clinical diagnostic laboratory or expert panel has classified this variant as pathogenic or likely pathogenic. OncoKB's 'Likely Oncogenic' designation is a somatic cancer biomarker annotation and does not constitute a germline variant classification suitable for PP5.	oncokb clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0.0). Does not meet the >1% population frequency threshold for BA1.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0.0). Does not meet the >0.3% population frequency threshold for BS1.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	The variant is absent from population databases; no observation in healthy adults, either homozygously or in trans with a known pathogenic variant, has been reported.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	No variant-specific functional studies demonstrating no deleterious effect have been identified. The five publications reviewed (PMID:11830484, 33951732, 34320176, 34448807, 38228680) discuss CEBPA mutations at the gene level but do not report functional data for c.926_928dupAGA. Full-text search of available papers confirmed the variant is not mentioned.
BS4	Not assessed	No cosegregation data are available to assess whether the variant fails to segregate with disease in affected families.
BP1	N/A	BP1 applies specifically to missense variants in genes where primarily truncating variants cause disease. This variant is an in-frame duplication, not a missense variant.
BP2	Not met	The variant has not been observed in trans with a known pathogenic variant in any database or publication.	gnomad_v2 gnomad_v4 clinvar
BP3	Not met	BP3 applies to in-frame deletions/insertions in repetitive regions without known function. This variant is in the bZIP domain, a region with well-established critical function for DNA binding and dimerization, and is not in a repetitive region.
BP4	Not met	Multiple lines of computational evidence suggesting no impact are not available. SpliceAI predicts no splice effect (max delta = 0.01), but REVEL and BayesDel are not applicable to indels. A single line of splice evidence is insufficient to meet BP4, and the variant's location in the bZIP functional domain does not support a benign computational prediction.	spliceai
BP5	Not met	The variant has not been observed in any case with an alternate molecular basis for disease. No such data are available.
BP6	Not met	No reputable source has classified this variant as benign or likely benign. The variant is absent from ClinVar entirely.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splice impact. This variant is an in-frame duplication, not a synonymous variant.
PM3	N/A	PM3 (observed in trans with a pathogenic variant) was not assessed per user direction — skipped as trivially not applicable.

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