The prevalence of DICER1 pathogenic variation in population databases

Abstract

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), 1000 Genomes (1000G), 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.

The prevalence of germline DICER1 pathogenic variation in cancer populations

“…In this study, for the first time, we have comprehensively quantified the prevalence of P/LP germline DICER1 variation in the largest publicly available sporadic adult and pediatric cancer cohorts. We observed an approximately twofold higher germline prevalence of the most damaging (pathogenic: LOF, splice, hotspot) of such variation in TCGA (9,173 subjects: 1:4,600) than was observed in non‐TCGA ExAC (53,103 subjects; 1:10,600) (Kim et al, ). In TCGA, we observed germline DICER1 LOF, splice and hotspot variation in individuals with uterine and rectal cancers, which are not known to be germline DICER1 ‐associated.…”

“…We used our published scheme to classify variants into pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), and likely benign (LB) categories (Kim et al, ). In brief, variants that are loss‐of‐function (LOF; e.g., nonsense and frameshift), located in the canonical splice site (≤2 intronic basepairs from the intron/exon boundary), missense located in DICER1 hotspots (e.g., E1705, D1709, G1809, D1810, E1813) or credibly reported as pathogenic in at least one publication are classified as P. Classification as LP required a nonsynonymous missense variant to be outside a DICER1 hotspot locus and harbor a bioinformatics pathogenicity prediction of “Deleterious” by metaSVM, a REVEL (Ioannidis et al, ) score >0.75, or a CADD (Kircher et al, ) score >30 (top 0.01% of the predicted deleteriousness).…”

DICER1 and Associated Conditions: Identification of At-risk Individuals and Recommended Surveillance Strategies

“…An analysis of the prevalence of pathogenic germline DICER1 variation in the Exome Aggregation Consortium (excluding cases ascertained from The Cancer Genome Atlas) found that approximately 1:2,529 – 1:10,600 individuals in the general population carry a pathogenic or likely pathogenic DICER1 variant. (38) The penetrance of each of the DICER1 -associated conditions is not fully understood. Lung cysts, presumably Type I or Type Ir PPB, and thyroid nodules appear to be the most common manifestations in individuals with germline loss-of-function mutations.…”

Ten years of DICER1 mutations: Provenance, distribution, and associated phenotypes

“…In this mutation update, we classified all catalogued variants ( n = 1136 total; n = 971 excluding germline variants that were not UPF) as either pathogenic/likely pathogenic, variants of uncertain significance (VUS), or benign/likely benign using a set of criteria outlined in the Supporting Information Materials, similar to those implemented by others (Kim, Field, Schultz, Hill, & Stewart, ): of the 313 germline UPF variants, 285 were considered pathogenic/likely pathogenic, 9 were VUSs, and 19 were considered benign/likely benign; all 15 mosaic mutations were pathogenic/likely pathogenic; and the 643 somatic alterations were comprised of 612 pathogenic/likely pathogenic mutations (including 512 RNase IIIb hotspot mutations), 14 VUSs, and 17 benign/likely benign mutations (Table S2). For comparative purposes, in Table S2, we have included the classification informed by the guidelines on sequence variant interpretation from the American College of Medical Genetics and Genomics (Richards et al, ) with which our classifications show high concordance.…”