NM_006231.4:c.-11C>T is a non-coding promoter/5'UTR substitution 11 bases upstream of the ATG start codon. It is present at extremely low frequency in gnomAD v4.1 (3/1,498,064 alleles, AF 0.00020%, all South Asian) and absent from gnomAD v2.1 and gnomAD-Canada, meeting PM2 at supporting level.¹ PVS1 does not apply as this is a non-coding variant and not a null variant. The León-Castillo 2020 custom POLE framework criteria (PM1, PS4, PP3, BP4) apply only to exonuclease-domain missense variants and do not extend to this promoter variant.² SpliceAI predicts no splice impact (max delta 0.00). No functional studies, segregation data, de novo reports, case-control data, or ClinVar classifications are available for this variant.³ No publications specifically mention NM_006231.4:c.-11C>T. Five papers reviewed in the PVS1 gene context support POLE loss-of-function as a germline disease mechanism at the gene level but do not report this specific variant. With only PM2_Supporting met, this variant does not meet any ACMG/AMP 2015 classification threshold (requires ≥2 pathogenic supporting criteria with additional evidence, or BS1/BA1 thresholds for benign classification). The variant is classified as a Variant of Uncertain Significance (VUS).⁴