NM_004364.3:c.47_48delinsA

CEBPA · NP_004355.2:p.(Ser16LysfsTer144) · NM_004364.3

GRCh37: chr19:33793273 GC>T · GRCh38: chr19:33302367 GC>T

Gene: CEBPA Transcript: NM_004364.3

Final call

VUS

PVS1 very strong PM2 supporting

Variant details

Gene

CEBPA

Transcript

NM_004364.3

Protein

NP_004355.2:p.(Ser16LysfsTer144)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

PVS1 (Very Strong): NM_004364.3:c.47_48delinsA is a frameshift null variant in CEBPA, a gene where loss-of-function is an established mechanism for autosomal dominant familial AML predisposition. The variant is predicted to produce p.Ser16LysfsTer144, ablating expression of the full-length p42 isoform. Assessed under ClinGen SVI PVS1 framework (PMC6185798).

PM2 (Supporting): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, consistent with a rare pathogenic variant.

Classification: Variant of Uncertain Significance (VUS). Met criteria: PVS1 (Very Strong) + PM2 (Supporting). Under generic ACMG/AMP 2015 final combination rules (PMID:25741868), 1 Very Strong + 1 Supporting does not reach the threshold for Likely Pathogenic (which requires at least 1 Very Strong + 1 Moderate, or 1 Strong + 2 Supporting). While the variant is strongly suggestive of pathogenicity based on its molecular consequence and absence from population databases, additional evidence (functional data, segregation, case observations, or ClinVar classification by an expert panel) would be needed to upgrade to Likely Pathogenic.

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	Met	Frameshift variant NM_004364.3:c.47_48delinsA (p.Ser16LysfsTer144) in exon 1 of CEBPA, a gene where loss-of-function is an established mechanism for autosomal dominant familial acute myeloid leukemia predisposition. The variant is predicted to cause premature termination at codon 159, ablating expression of the full-length p42 isoform. Germline loss-of-function disease mechanism confirmed by literature review supporting CEBPA as a germline predisposition gene (WHO 5th edition myeloid neoplasm classification). Assessed under ClinGen SVI PVS1 framework (PMC6185798).	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies to same amino acid change as a previously established pathogenic missense variant. This variant is a frameshift, not a missense change.
PS2	Not assessed	No de novo data available for this variant.
PS3	Not assessed	Five papers on N-terminal CEBPA mutations and p30 isoform function were reviewed in full text or abstract. None mention the specific variant NM_004364.3:c.47_48delinsA or p.Ser16LysfsTer144. While these papers demonstrate that N-terminal CEBPA frameshifts leading to p30 expression are pathogenic in somatic AML, no variant-specific functional data exist for this exact variant.
PS4	Not assessed	No case-control data or prevalence comparison available for this variant.
PS5	N/A	PS5 is not applicable to frameshift variants. PS5 evaluates a different nucleotide change at the same position as a known pathogenic variant, which is a missense-only concept.
PM1	Not met	Variant does not lie in a statistically significant mutational hotspot as assessed by cancerhotspots.org. Although CEBPA N-terminal mutations cluster in AML, the exact residue (Ser16) is not flagged as a significant hotspot residue.
PM2	Met	Variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases, consistent with a rare pathogenic variant. Under generic ACMG/AMP 2015 rules, PM2 is met at supporting strength (allele frequency <0.1%).	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Skipped per adjudication instructions.
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants. This variant is a frameshift and does not qualify for PM4.
PM5	N/A	PM5 requires a known pathogenic missense change at the same residue. This variant is a frameshift and cannot be evaluated under PM5. Automated PM5 candidate harvesting confirmed: unable to establish same-residue comparator semantics.	pm5_candidates
PM6	Not assessed	No de novo data with or without confirmed maternity/paternity available for this variant.
PP1	Not assessed	No cosegregation data available for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This is a frameshift variant.
PP3	Not met	SpliceAI predicts no splice-altering effect (max delta score = 0.00). REVEL and BayesDel are not applicable to indels. No in silico evidence supports a deleterious effect beyond the established truncation mechanism. For a frameshift variant, the primary pathogenic mechanism is protein truncation, which is already captured by PVS1 and should not be double-counted with PP3.	spliceai
PP4	Not assessed	No patient phenotype data available to assess specificity of clinical presentation.
PP5	Not met	Variant is absent from ClinVar and has not been classified by any germline diagnostic laboratory or expert panel. OncoKB classifies this variant as Likely Oncogenic, but this is a somatic oncology annotation and does not constitute a reputable germline variant classification source for PP5 under ACMG/AMP guidelines.	clinvar oncokb
BA1	Not met	Variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada). Allele frequency is 0%, well below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Variant is absent from all population databases. Allele frequency is 0%, well below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data on observation of this variant in healthy adults available. BS2 requires a variant to be observed in a healthy adult individual for a fully penetrant dominant disorder.
BS3	Not assessed	Five papers on CEBPA N-terminal mutations were reviewed (full text for PMID:31309149 and PMID:31867767; abstracts for PMID:17242690, 17671234, 20884804). All describe N-terminal frameshift mutations as pathogenic/likely pathogenic in AML via p30-mediated mechanisms. None contain variant-specific functional evidence showing a benign effect for this variant. BS3 requires well-established functional studies showing no damaging effect, which is not applicable here as the available functional literature supports a deleterious role for this class of mutations.
BS4	Not assessed	No segregation data available. BS4 requires lack of segregation in affected family members.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary pathogenic mechanism. This variant is a truncating (frameshift) variant, not a missense.
BP2	Not assessed	No data on observation of this variant in trans with a known pathogenic variant.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions. This is a frameshift variant.
BP4	N/A	BP4 applies when multiple lines of computational evidence suggest no impact on gene or gene product. This is a frameshift variant with a clear protein-truncating effect; in silico splicing predictions (SpliceAI delta = 0.00) do not address the primary mechanism of protein truncation and are not sufficient to apply BP4.
BP5	Not assessed	No data on observation of this variant in a case with an alternate molecular basis for disease.
BP6	Not met	Variant is absent from ClinVar and has not been classified as benign or likely benign by any reputable source.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splicing impact. This is a frameshift variant.

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.