DICER1 is a highly conserved RNase III endoribonuclease that plays a central role in microRNA (miRNA) biogenesis and RNA interference 1. The enzyme cleaves long double-stranded RNAs and pre-miRNA hairpins into 21-23 nucleotide fragments, generating mature miRNAs and small interfering RNAs (siRNAs) that regulate post-transcriptional gene silencing of more than half of human protein-coding genes 1. These processed RNAs direct the RNA-induced silencing complex (RISC) to complementary RNA targets for degradation or translational repression, controlling transposon activity and exogenous viral RNA 1. Germline pathogenic DICER1 variants cause DICER1 syndrome, a tumor predisposition syndrome with unusual two-hit genetics where individuals require only haploinsufficiency plus a second somatic missense mutation at specific hotspot codons 1. The syndrome exhibits incomplete penetrance and broad phenotypic heterogeneity, with up to 30 associated neoplastic conditions 2. Most prevalent are pleuropulmonary blastoma, Sertoli-Leydig cell tumors, multinodular goiter, cystic nephroma, and embryonal rhabdomyosarcoma 3. DICER1 hotspot mutations in cancer compromise RNase function, causing both loss of canonical miRNA-5p strands and paradoxical gain-of-function through selective upregulation of miRNA-3p passenger strands with increased Argonaute loading and repression capacity 4. Prevalence of germline DICER1 variants is approximately 1:30 in pediatric cancer predisposition populations, with thyroid alterations being common in adult carriers 5.