PM1 (moderate): The variant alters serine 33, a critical GSK-3β phosphorylation residue within the N-terminal degron motif of β-catenin — a well-established functional domain where missense mutations cause constitutive Wnt pathway activation. The residue is identified as a statistically significant mutational hotspot.¹ PM2 (moderate): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with a variant not tolerated in the general population.² PS3 (supporting): Functional studies demonstrate that S33F disrupts GSK-3β phosphorylation, leading to β-catenin stabilization and nuclear accumulation. In colorectal cancer tissue, the mutation was confirmed to cause increased β-catenin protein expression.³ The combined evidence (PM1 + PM2 + PS3) yields two moderate and one supporting criterion. Per ACMG/AMP 2015 generic combination rules (PMID:25741868), this does not reach the Likely Pathogenic threshold, which requires ≥3 moderate or ≥2 moderate plus ≥2 supporting criteria. The variant is classified as a Variant of Uncertain Significance (VUS).⁴ This variant (S33F) is a well-established somatic oncogenic driver in multiple cancer types (COSMIC count: 199; pilomatricoma, medulloblastoma, colorectal cancer, hepatocellular carcinoma) but has not been reported as a germline disease-causing variant. It is absent from population databases. Germline CTNNB1 syndrome is primarily associated with loss-of-function truncating variants, not the exon 3 degron missense mutations that characterize somatic oncogenesis.⁵