The PTEN c.722T>C (p.Phe241Ser) variant has been observed in somatic cancers in COSMIC (COSV64294827, 5 occurrences) and has not been reported in the current ClinVar record set.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, with an observed allele frequency of 0, which is below the PTEN Expert Panel PM2_Supporting threshold of <0.00001 (0.001%).² Functional studies support a damaging effect on PTEN, including a Mighell et al. phosphatase assay result of Cum_score -2.399 with High_conf=True, which is below the PTEN Expert Panel PS3_Moderate threshold of <= -1.11; OncoKB also describes the variant as Likely Oncogenic with a likely loss-of-function effect.³ Computational evidence supports a deleterious effect for the missense change because the REVEL score is 0.858, above the PTEN Expert Panel PP3 threshold of >0.7, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.01.⁴