NM_000314.8:c.544T>G (p.Leu182Val) is a missense variant in exon 6 of PTEN. It is absent from gnomAD v2.1 and v4.1 (0/1,612,242 alleles), meeting PM2_Supporting per the PTEN VCEP threshold of <0.001%.¹ In the Mighell et al. 2018 (PMID:29706350) saturation mutagenesis functional assay, L182V has a cumulative fitness score of -1.24 (High_conf=True), meeting the PTEN VCEP PS3_Moderate threshold of Cum_score <= -1.11, indicating a damaging effect on PTEN phosphatase activity.² PTEN is a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease (PHTS, autosomal dominant). PP2 is applied at Supporting level per the PTEN VCEP specification.³ L182V REVEL score is 0.682, below the PTEN VCEP PP3 threshold of >0.7, and above the BP4 missense threshold of <0.5. Computational evidence is indeterminate and does not contribute to either pathogenic or benign criteria.⁴ The variant lies outside PTEN catalytic motifs (WPD loop 90-94, P-loop 123-130, TI-loop 166-168). PM1 is not met.⁵ L182S (c.545T>C) is a pathogenic ClinVar missense at the same residue, but PM5 is not met because the BLOSUM62 score for Leu->Val (+1) is greater than Leu->Ser (-2), failing the VCEP BLOSUM62 requirement.⁶ No proband, segregation, de novo, or case-control data are available. PS2, PS4, PM6, PP1, BS4, BP2, and BP5 are not met. Criteria not applicable per the PTEN VCEP include PVS1 (missense, not null), PP4, PP5, BP1, BP6, and BP7.⁷ Overall, met criteria: PS3_Moderate (1 moderate), PM2_Supporting (1 supporting), PP2 (1 supporting). This yields 1 moderate + 2 supporting pathogenic criteria with no benign criteria. Under the PTEN VCEP/ACMG 2015 combination rules, Likely Pathogenic requires at least 3 moderate, or 2 moderate + >=2 supporting, or 1 strong + >=2 supporting, or 1 strong + 1 moderate. With only 1 moderate + 2 supporting, none of the Pathogenic or Likely Pathogenic rules are satisfied. The variant is classified as a Variant of Uncertain Significance (VUS).⁸