NM_006231.4:c.6748-18G>A is an intronic variant in POLE located 18 bases upstream of exon 48. This variant has been observed at very low frequency in population databases (gnomAD v2.1: 8/249,726 alleles, AF=0.0032%; gnomAD v4.1: 13/1,594,924 alleles, AF=0.00082%) with no homozygotes.¹ The variant meets PM2 (Supporting) due to its very low population frequency, below the 0.1% threshold.² SpliceAI predicts no impact on splicing (max delta score = 0.00), and no other computational tools predict a deleterious effect. PP3 is not met and BP4 does not reach the 'multiple lines' threshold.³ This variant has been reported in ClinVar as Likely benign by Labcorp Genetics (formerly Invitae), meeting BP6 (Supporting).⁴ The variant is not located in a known POLE mutational hotspot or functional domain. The custom POLE framework (León-Castillo et al. 2020) applies exclusively to missense variants and does not provide applicable PM1, PS4, PP3, or BP4 rules for this intronic variant.⁵ No functional studies, segregation data, de novo observations, or case-control data are available. PVS1 is not applicable as the variant does not meet null-variant criteria. PS1, PM5, PP2, BP1, and BP7 are not applicable due to the intronic nature of the variant.⁶ The evidence profile consists of one pathogenic supporting criterion (PM2) and one benign supporting criterion (BP6), resulting in a variant of uncertain significance (VUS) under the custom POLE framework using generic ACMG/AMP 2015 combination rules.⁷