Submission Details

DICER1-related tumor predisposition was first described in families with pleuropulmonary blastoma, a rare pediatric lung tumor (Hill et al., PMID:19556464). The phenotypic spectrum has subsequently expanded to include a wide range of benign and malignant neoplasms in both children and adults such as thyroid cancer, cystic nephroma, multinodular goiter, ovarian and Sertoli cell tumors and lung cyst. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found DICER1-related tumor predisposition syndrome (MONDO:0100216) is the only disease entity associated with this gene. The DICER1 gene is reported to be instrumental in miRNA processing, and publications indicate that DICER1 variants impact double stranded miRNA processing and specifically impair 5p-derived miRNA production (PMID:24909177). DICER1 syndrome is proposed to occur due to a global alteration in miRNA mRNA targets towards a malignant/transformative phenotype after specific somatic missense variants in the RNase IIIB domain occur in DICER1 (PMID: 30956758, 30967628). Multiple types of evidence support the relationship between DICER1 and DICER1-related tumor predisposition syndrome, including numerous case-level data, and experimental data across a range of areas. More evidence is available in the literature but the maximum score for genetic evidence (12 points) has been reached. This gene-disease curation reports 18 variants in 18 probands in 6 publications, (PMIDs: 19556464, 21266384, 28222777, 33567437, 26545620, 27896549). The gene-disease relationship is also supported by experimental evidence (5 points) in animal models, in vitro functional assays and rescue experiments. Complete Dicer1 knockout in mice results in embryonic lethality indicating the broad importance of Dicer1, while conditional knockout models support a role for Dicer1 in murine lung development, specifically in branching morphogenesis (PMID:16452165). In addition, models of heterozygous and conditional Dicer1 deletion show tumor development phenotypes consistent with DICER1-related tumor predisposition syndrome (PMID: 15713842). Rescue studies indicate both phenotype and functional mechanisms are repaired after Human DICER1 replacement in Dicer1 loss mice (PMID: 28446596). In summary, DICER1 is definitively associated with autosomal dominant DICER1-related tumor predisposition syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.