NM_005378.5:c.1340T>C (p.Leu447Ser) is a missense variant in MYCN, located within the C-terminal leucine zipper domain critical for protein dimerization and DNA binding. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.¹ PM1 (moderate) is met: residue Leu447 lies within the MYCN leucine zipper domain, a well-established critical functional domain. The variant is absent from population databases, consistent with a lack of benign variation in this region.² PM2 (supporting) is met: the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency <0.1%).³ PVS1 is not applicable: the variant is a missense substitution and does not qualify as a predicted null variant under PMC6185798.⁴ PP3 is not met: in silico predictors are conflicting (REVEL 0.767 damaging, BayesDel 0.164 neutral). BP4 is also not met for the same reason.⁵ BP1 is not met: missense variants in MYCN are a known disease mechanism for Feingold syndrome type 1 and megalencephaly-polydactyly syndrome. With one moderate criterion (PM1) and one supporting criterion (PM2), this combination does not reach the Likely Pathogenic threshold under generic ACMG/AMP 2015 combination rules (PMID:25741868). The variant is classified as a Variant of Uncertain Significance (VUS).⁶