The prevalence of DICER1 pathogenic variation in population databases

Int J Cancer. 2017 Nov 15;141(10):2030-2036. doi: 10.1002/ijc.30907. Epub 2017 Aug 21.


The DICER1 syndrome is associated with a variety of rare benign and malignant tumors, including pleuropulmonary blastoma (PPB), cystic nephroma (CN) and Sertoli-Leydig cell tumor (SLCT). The prevalence and penetrance of pathogenic DICER1 variation in the general population is unknown. We examined three publicly-available germline whole exome sequence datasets: Exome Aggregation Consortium (ExAC), 1,000 Genomes (1,000 G) and the Exome Sequencing Project (ESP). To avoid over-estimation of pathogenic DICER1 variation from cancer-associated exomes, we excluded The Cancer Genome Atlas (TCGA) variants from ExAC. All datasets were annotated with snpEff and ANNOVAR and variants were classified into four categories: likely benign (LB), unknown significance (VUS), likely pathogenic (LP), or pathogenic (P). The prevalence of DICER1 P/LP variants was 1:870 to 1:2,529 in ExAC-nonTCGA (53,105 exomes) estimated by metaSVM and REVEL/CADD, respectively. A more stringent prevalence calculation considering only loss-of-function and previously-published pathogenic variants detected in ExAC-nonTCGA, yielded a prevalence of 1:10,600. Despite the rarity of most DICER1 syndrome tumors, pathogenic DICER1 variation is more common than expected. If confirmed, these findings may inform future sequencing-based newborn screening programs for PPB, CN and SLCT, in which early detection improves prognosis.

Keywords: DICER1; DICER1 syndrome; Sertoli-Leydig cell tumor; pleuropulmonary blastoma; prevalence estimates.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Intramural

MeSH terms

  • Biomarkers / metabolism*
  • DEAD-box RNA Helicases / genetics*
  • Early Detection of Cancer
  • Female
  • Genetic Predisposition to Disease
  • Germ-Line Mutation
  • Humans
  • Kidney Diseases, Cystic / epidemiology
  • Kidney Diseases, Cystic / genetics*
  • Ovarian Neoplasms / epidemiology
  • Ovarian Neoplasms / genetics*
  • Prevalence
  • Prognosis
  • Pulmonary Blastoma / epidemiology
  • Pulmonary Blastoma / genetics*
  • Ribonuclease III / genetics*
  • Sertoli-Leydig Cell Tumor / epidemiology
  • Sertoli-Leydig Cell Tumor / genetics*
  • United States / epidemiology


  • Biomarkers
  • DICER1 protein, human
  • Ribonuclease III
  • DEAD-box RNA Helicases

Supplementary concepts

  • Pleuropulmonary blastoma