PTEN c.238A>G (p.Lys80Glu) is a missense variant in exon 4 of the phosphatase domain. The variant is absent from population databases (gnomAD v2.1 and v4.1), meeting PM2_Supporting per PTEN VCEP.¹ Functional data from Mighell et al. 2018 (PMID: 29706350) saturation mutagenesis assay demonstrates a cumulative fitness score of -1.60681967, below the -1.11 threshold for PS3_Moderate, indicating significantly reduced phosphatase activity with high confidence.² Computational evidence supports pathogenicity: REVEL score 0.775 (>0.7 threshold for PP3) per PTEN VCEP specification.³ PP2 is applied as PTEN has a low rate of benign missense variation and missense variants are a common disease mechanism.⁴ No benign criteria are met: variant is absent from population databases (BA1/BS1 not met), no homozygous observations (BS2 not met), functional data shows damaging effect (BS3 not met), REVEL exceeds benign threshold (BP4 not met).⁵ Under the PTEN VCEP v3.2.0 combination rules, this evidence set (PS3_Moderate + PM2_Supporting + PP2 + PP3 = 1 moderate + 3 supporting) does not trigger any Pathogenic or Likely Pathogenic classification rule. The variant is classified as Variant of Uncertain Significance (VUS).⁶