Submissions for variant NM_177438.3(DICER1):c.5113G>A (p.Glu1705Lys)

dbSNP: rs1890101390

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	RCV001200970	SCV004231829	pathogenic	DICER1-related tumor predisposition	2024-01-09	reviewed by expert panel	curation	The NM_177438.2:c.5113G>A variant in DICER1 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 1705 (p.Glu1705Lys). This variant has been identified as a de novo occurrence with constitutional mosaicism in one individual with pleuropulmonary blastoma type I and cystic nephroma (PS2; PS4_supporting; 26925222). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting). In vitro cleavage assays performed in different cell lines have demonstrated that this variant fails to produce 5p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (PS3_Supporting; 22187960, 23132766, 28862265). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.925) (PP3). This variant resides in the p.E1705 metal ion-binding residue located in the RNase IIIb domain of DICER1, that is defined as a mutational hotspot and critical functional domain by the ClinGen DICER1 VCEP (PM1; PMID: 31342592). In summary, this variant meets the criteria to be classified as Pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS2, PM2_Supporting, PS4_supporting, PS3_Supporting, PP3, PM1. (Bayesian Points: 10; VCEP specifications version 1.2.0; 01/09/2024).
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV001200970	SCV001371938	pathogenic	DICER1-related tumor predisposition	2019-07-01	criteria provided, single submitter	curation	ACMG criteria met: PS2, PS3, PM1, PM2, PP4
Ambry Genetics	RCV002348647	SCV002645553	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-23	criteria provided, single submitter	clinical testing	The p.E1705K variant (also known as c.5113G>A), located in coding exon 23 of the DICER1 gene, results from a G to A substitution at nucleotide position 5113. The glutamic acid at codon 1705 is replaced by lysine, an amino acid with similar properties. This alteration has been reported as mosaic in normal ureter tissue of a child with a personal history of a pleuropulmonary blastoma and cystic nephroma (Brenneman M et al. F1000Res, 2015 Jul;4:214). Functional studies have shown that DICER1 p.E1705K exhibits defects in miRNA processing (Heravi-Moussavi A et al. N Engl J Med, 2012 Jan;366:234-42). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.