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).¹ PM2 (Supporting): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, consistent with a rare pathogenic variant.² 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.³