NM_033632.3:c.1697G>T (p.Trp566Leu) is a missense variant in exon 11 of FBXW7, affecting the WD40 repeat domain critical for substrate recognition. The variant is completely absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_Supporting).¹ FBXW7 germline loss-of-function and missense variants are established causes of an autosomal dominant neurodevelopmental syndrome with Wilms tumor predisposition (PMID:35395208). The variant alters a highly conserved tryptophan residue within the WD40 domain where pathogenic missense variants cluster (PMID:42111496), though no formal VCEP domain specification exists. The variant has been reported twice in somatic cancers (COSMIC COSV99662097), consistent with a role in tumorigenesis.² REVEL predicts a damaging score of 0.863, though BayesDel (0.424) does not reach the damaging threshold, and no variant-specific functional studies were identified. Computational evidence alone is insufficient to meet PP3.³ No ClinVar entries, no published variant-specific functional studies, no segregation or de novo data, and no case-control evidence exist for this variant. The variant remains unclassified in all major clinical databases.⁴