NM_005228.4:c.2146A>G (p.Lys716Glu) is a missense variant in EGFR exon 18, encoding part of the kinase domain ATP-binding pocket. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_supporting).¹ In silico predictions are indeterminate: REVEL score 0.426 and BayesDel score 0.075 fall between benign and pathogenic thresholds; SpliceAI predicts no splicing impact (max delta 0.00). Neither PP3 nor BP4 is met.² The variant has been reported once in a somatic context in a patient with lung adenocarcinoma enrolled in a study of non-classical EGFR mutations; p.Lys716Glu was classified as a resistant mutation to afatinib (progressive disease, PFS 1.1 months) (PMID:28676220). This observation does not meet PS3 or PS4 thresholds in a germline variant interpretation context.³ No experimental functional data, no segregation data, no de novo reports, and no pathogenic ClinVar classifications exist for this variant. ClinVar reports Uncertain significance from two clinical laboratories.⁴ With a single supporting-level criterion (PM2_supporting) and no other criteria met in either the pathogenic or benign direction, this variant is classified as a Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 combination rules.⁵