NM_001127511.3:c.3865del (p.Ile1289Ter) is a frameshift deletion producing a premature termination codon at residue 1289 in the APC gene, where loss of function is the established mechanism for familial adenomatous polyposis (PVS1_VeryStrong). The truncation removes more than half of the protein including all critical C-terminal domains required for beta-catenin regulation and tumor suppression.¹ This variant is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the APC VCEP threshold for PM2_Supporting (allele count ≤ 1, AF < 0.001%).² Under the InSiGHT APC VCEP v2.1 combination rules (Rule 20), one PVS1_VeryStrong criterion combined with one supporting pathogenic criterion (PM2_Supporting) yields a classification of Likely Pathogenic.³ OncoKB classifies this variant as Likely Oncogenic with a Likely Loss-of-function biological effect, consistent with the predicted truncating impact.⁴