NM_006219.2:c.3200A>T (p.Asp1067Val) is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0.0).¹ The variant is absent from ClinVar and has no germline classification from any submitter.² Asp1067 resides in the C-terminal kinase domain of PIK3Cβ and lies within a statistically significant mutational hotspot (cancerhotspots.org). PMID:25982275 reports that D1067V is the most recurrent missense mutation in the PIK3Cβ kinase domain, accounting for ~15% of kinase domain missense mutations, and that D1067 is highly conserved across species.³ Functional studies in PMID:25982275 demonstrate that PIK3Cβ/D1067V is a gain-of-function activating mutation in somatic cancer models (enhanced AKT/S6 phosphorylation, increased cell growth in vitro, tumor formation in vivo, erlotinib resistance). This evidence was not applied toward PS3 because the demonstrated gain-of-function mechanism does not align with the reported germline loss-of-function disease mechanism.⁴ REVEL score of 0.65 suggests possible pathogenicity, but BayesDel (0.313) is borderline and SpliceAI predicts no splicing impact (max delta = 0.00). In silico evidence does not provide multiple converging lines for PP3 or BP4.⁵ The variant has been observed 16 times in somatic cancers (COSMIC COSV56683107) and is classified as Oncogenic by OncoKB, but these pertain to somatic context and are not directly applicable to germline classification.⁶ Two moderate pathogenicity criteria are met: PM1 (kinase domain hotspot) and PM2 (absent from population databases). No benign criteria are met. Per generic ACMG/AMP 2015 combination rules, two moderate criteria in the absence of benign criteria yields a classification of Likely Pathogenic.⁷