NM_000314.8:c.413A>G (p.Tyr138Cys) is a missense variant in exon 5 of PTEN. It is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada), satisfying PM2_Supporting per PTEN VCEP criteria.¹ Functional evidence from Mighell et al. 2018 (PMID:29706350) saturation mutagenesis demonstrates that Y138C has a cumulative fitness score of -1.766, meeting the PTEN VCEP threshold of ≤ -1.11 for PS3_Moderate. Independently, Tibarewal et al. 2012 (PMID:22375056) characterized Y138C and demonstrated that it retains lipid phosphatase activity but selectively lacks protein phosphatase activity, with failure to suppress cellular invasion — confirming a damaging functional effect.² Computational evidence supports pathogenicity: REVEL score 0.962 (>0.7, meeting PP3 threshold per PTEN VCEP). PTEN has a low rate of benign missense variation and missense variants are a known disease mechanism for PTEN hamartoma tumor syndrome (PP2 per VCEP).³ The variant is classified as Uncertain Significance in ClinVar (variation ID 486230) by all four submitting clinical laboratories. It has been observed in somatic cancers (COSMIC, n=6).⁴ Applying the PTEN VCEP classification rules: 1 moderate pathogenic criterion (PS3_Moderate) and 3 supporting pathogenic criteria (PM2_Supporting, PP2, PP3) are met. No benign criteria are met. Per the VCEP combination rules, this evidence profile does not reach the Likely Pathogenic threshold (requires ≥3 moderate, or 2 moderate + ≥2 supporting, or 1 strong + 1 moderate, or 1 moderate + ≥4 supporting). The variant is classified as a Variant of Uncertain Significance (VUS).⁵ Key gap: the Mighell et al. functional data for Y138C has a High_conf=False quality flag ('Fail Both'), indicating the measurement did not pass high-confidence filters. Additional functional validation, segregation data, de novo observations, or clinical case-level phenotype data could resolve this VUS.⁶