NM_000314.8:c.106G>C (p.Gly36Arg) is a missense variant in PTEN, a tumor suppressor gene where loss-of-function is an established mechanism for PTEN hamartoma tumor syndrome (autosomal dominant).¹ The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting PM2_Supporting under PTEN VCEP criteria (allele frequency < 0.001%).² Functional data from Mighell et al. 2018 saturation mutagenesis (PMID:29706350, VCEP mmc2.xlsx Table S2) show G36R with a cumulative fitness score of -2.69 (High_conf=True), meeting the VCEP PS3_Moderate threshold of ≤ -1.11.³ An independent functional study (PMID:10772390) reported that the same amino acid change p.Gly36Arg (produced by c.106G>A) resulted in approximately 90% loss of PTEN phosphatase activity in a recombinant assay.⁴ REVEL score is 0.995 (> 0.7 VCEP threshold), meeting PP3 at Supporting strength. PP2 is met at Supporting as PTEN has a low rate of benign missense variation and missense variants are a common disease mechanism.⁵ ClinVar VariationID 189400 (encompassing c.106G>C and c.106G>A, both p.Gly36Arg) is classified as Likely pathogenic by the ClinGen PTEN VCEP (reviewed by expert panel), with one clinical laboratory submitting as Pathogenic and one as Uncertain significance.⁶ Combined evidence: 1 moderate pathogenic criterion (PS3_Moderate) and 3 supporting pathogenic criteria (PM2_Supporting, PP2, PP3). Under the ClinGen PTEN VCEP v3.2.0 classification framework, this combination does not meet any pathogenic or likely pathogenic rule. The variant is classified as Uncertain Significance (VUS).⁷