PVS1 (very strong) is met: NM_012289.4:c.542_543insT is a frameshift insertion in exon 2 of 6 creating a premature termination codon at position 192 (NP_036421.2:p.(Ser182GlnfsTer11)), predicted to trigger nonsense-mediated decay. KEAP1 loss of function is an established germline disease mechanism, supported by published pathogenic frameshift variants causing familial multinodular goiter (PMID:39373520).¹ PM2 (supporting) is met: the variant is completely absent from gnomAD v2.1 and v4.1 population databases, consistent with a rare pathogenic variant.² No additional pathogenic criteria are met. The variant has not been reported in affected individuals (PS4 not met), no functional studies are available for this exact variant (PS3 not assessed), no de novo observations exist (PS2/PM6 not met), and no segregation or case-level data is available (PP1/PP4 not met). No benign criteria are met. The variant is absent from population databases (BA1/BS1 not met), and no functional or clinical evidence supports a benign interpretation.³ Under generic ACMG/AMP 2015 combination rules (PMID:25741868), PVS1 (very strong) + PM2 (supporting) does not reach a Likely Pathogenic or Pathogenic threshold. The minimum requirement for Likely Pathogenic with PVS1 is one additional moderate criterion, which is not met. The classification is therefore Variant of Uncertain Significance (VUS).⁴