NM_017617.5:c.5353G>T (NP_060087.3:p.Glu1785Ter) is a nonsense variant in exon 28 of 34 in NOTCH1, predicted to result in premature termination and nonsense-mediated decay, triggering loss of function. NOTCH1 loss of function is an established disease mechanism for autosomal dominant Adams-Oliver syndrome and congenital heart defects, with ClinGen haploinsufficiency score 3 (PVS1).¹ The variant is absent from gnomAD v2.1 and v4.1 (0/1,612,390 alleles) and from all population subpopulations, meeting PM2.² No case reports, segregation data, de novo observations, or functional studies specific to this variant were identified. The variant is absent from ClinVar. Five OncoKB-linked publications discuss NOTCH1 loss-of-function in somatic squamous cell carcinomas but none mention this specific variant. Under ACMG/AMP 2015 combination rules, one very strong (PVS1) and one moderate (PM2) criterion yields a classification of Pathogenic.³