NM_004119.3:c.1792_1793insACCTTCCTGTGACCGGCTCCTCAGATAATGAGTACTTCTACGTTGATTTCAGAGAATATG (p.Tyr597_Glu598insAspLeuProValThrGlySerSerAspAsnGluTyrPheTyrValAspPheArgGluTyr) is a novel 20-amino-acid in-frame internal tandem duplication (ITD) in the FLT3 juxtamembrane domain at codons 597-598, within the well-established ITD activating hotspot (codons 589-599).¹ PM1_Moderate is met because the variant maps to the FLT3 juxtamembrane ITD hotspot (codons 589-599), a critical functional domain where recurrent activating ITDs have been established and where no benign population variation is observed in gnomAD. PMID:9737679 documented 47 of 51 FLT3 ITDs in this same codon cluster with constitutive kinase activation.² PM5_Moderate is met per the local FLT3 custom framework extension: this is a novel ITD in the same established activating juxtamembrane hotspot class as prior pathogenic FLT3 ITDs. The exact inserted sequence need not have been previously characterized; the event is clearly an ITD analogue in the same hotspot mechanism as established activating FLT3 mutations.³ PS3_Supporting is met because OncoKB reports exact-variant Likely Oncogenic with Likely Gain-of-function for p.(Y597_E598insDLPVTGSSDNEYFYVDFREY), and the broader FLT3 ITD literature (PMID:9737679, PMID:11090077, PMID:11756186) establishes constitutive kinase activation as the canonical mechanism for juxtamembrane ITDs.⁴ PM2_Supporting is met because the variant is absent from gnomAD v2.1 and v4.1 (allele frequency 0.0% in all populations).⁵ The variant is absent from ClinVar and COSMIC. SpliceAI predicts an acceptor gain (delta 0.45), but this is of uncertain clinical significance for an in-frame ITD with an established gain-of-function mechanism.⁶ Applying the local FLT3 ITD / activating length-mutation framework with generic ACMG/AMP 2015 final combination rules: 2 Moderate criteria (PM1, PM5) plus 2 Supporting criteria (PS3, PM2) meets the threshold for Likely Pathogenic (2 Moderate + >=2 Supporting).⁷