NM_000314.8:c.532T>G (p.Tyr178Asp) is a missense variant in PTEN exon 6. This variant is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).¹ Functional assessment via saturation mutagenesis phosphatase activity assay (Mighell et al. 2018, PMID: 29706350) demonstrates a cumulative fitness score of -4.72, well below the VCEP PS3_Moderate threshold of <= -1.11, with high-confidence measurement (PS3_Moderate).² Computational predictions support a deleterious effect: REVEL score of 0.958 exceeds the VCEP PP3 threshold of > 0.7 (PP3). PTEN has a low rate of benign missense variation and missense variants are a common disease mechanism (PP2).³ This variant has been reported in ClinVar as Uncertain significance by a single submitter (VCV000945254) and in COSMIC as a somatic variant (COSV64304856, n=1). OncoKB classifies it as Likely Oncogenic in the somatic context.⁴ Position 178 is outside the VCEP-defined PM1 catalytic motifs (WPD loop 90-94, P-loop 123-130, TI-loop 166-168). No alternate pathogenic missense at residue 178 was identified for PM5. No de novo, cosegregation, or case-control data are available.⁵ Applying the PTEN VCEP v3.2 combination rules: one moderate criterion (PS3_Moderate) and three supporting criteria (PM2_Supporting, PP2, PP3) are met. No combination rule for Likely Pathogenic is satisfied (Rule 13 requires >=3 moderate; Rule 14 requires 2 moderate + >=2 supporting; Rule 15 requires 1 moderate + >=4 supporting). The variant is classified as Uncertain Significance.⁶