The PHF6 c.1000G>T (p.Glu334Ter) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, with an observed allele frequency of 0 in both datasets, which is below the 0.1% rarity threshold used to support PM2 at supporting strength.² PHF6 loss of function is an established disease mechanism, and this nonsense variant is predicted to truncate the protein from 366 to 334 amino acids; however, because the change lies in the last coding exon and removes only the distal C-terminal portion, PVS1 remains for manual review rather than automatic application.³ SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00.⁴