PM2_Supporting: This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the VCEP threshold of ≤1 individual in population databases.¹ PP2_Supporting: PIK3CA has a missense constraint Z-score of 4.07 in gnomAD v2.1, exceeding the VCEP threshold of >3.09, indicating a low rate of benign missense variation.² PS1 is not met: no alternative nucleotide change at codon 681 producing p.Ser681Thr has been established as pathogenic.³ PM1 is not met: residue Ser681 at position 681 falls outside the VCEP Table 4 approved kinase domains for PIK3CA (AA 322-483 and AA 797-1068).⁴ PS3 and BS3 are not met: no variant-specific functional studies are available. OncoKB classifies p.Ser681Thr as Unknown Oncogenic Effect.⁵ PS4 is not met: no affected individuals with this variant have been reported; no phenotype points can be scored under VCEP Tables 2A/2B.⁶ Six publications were reviewed; none mention NM_006218.4:c.2042G>C or PIK3CA p.Ser681Thr.⁷ Using the Brain Malformations VCEP Tavtigian point framework (Path Supporting +1, Path Moderate +2, Path Strong +4, Path Very Strong +8; Benign Supporting -1, Mod -2, Strong -4, Very Strong -8), the total score is +2 (PM2_Supporting +1, PP2_Supporting +1), which falls within the VUS range (0-5 points).⁸