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.1 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.2 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. 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.3
CEBPA
Final classification
Likely Pathogenic
CEBPA c.926_928dup · p.Glu309_Thr310insLys
CEBPA
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.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 moderate, PM4 moderate; combination = 3 moderate, which maps to Likely Pathogenic.
Classification rationale
PM1PM2PM4
Likely Pathogenic
CEBPA c.926_928dup
PM1 + PM2 + PM4
→
Likely Pathogenic
Gene diagram
· NM_004364.3 · variants mapped to exon structure
CEBPA
NM_004364.3
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
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 = 0.01).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57195593, n = 9 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 5 PMIDs not cited in assessment
11830484 ↗
Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias.
ONCOKB
33951732 ↗
CEBPA-bZip mutations are associated with favorable prognosis in de novo AML: a report from the Children's Oncology Group.
ONCOKB
34320176 ↗
CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome.
ONCOKB