Submissions for variant NM_177438.3(DICER1):c.5125G>A (p.Asp1709Asn)

dbSNP: rs1595331264

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	RCV001200976	SCV002540836	pathogenic	DICER1-related tumor predisposition	2022-05-17	reviewed by expert panel	curation	The NM_177438.2:c.5125G>A variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 1709 (p.Asp1709Asn). This variant received a total of 2 phenotype points across 2 unrelated probands meeting DICER1 VCEP phenotype specificity scoring criteria of 2-3.5 points (PS4_Moderate, PMIDs: 26925222, 26475046). In both probands, this variant was identified as a de novo occurrence with constitutional mosaicism (PS2_Very Strong; PMIDs: 26925222, 26475046). This variant is absent from gnomAD v2.1.1 and v3.1.1 (non-cancer) (PM2_Supporting). In vitro cleavage assays in HEK293 cells showed that this variant fails to produce 5p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (PS3_Supporting, PMIDs: 22187960, 26545620). The computational predictor REVEL gives a score of 0.868, which is above the threshold of 0.75, evidence that correlates with impact to DICER1 function (PP3). This variant resides in the p.D1709 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 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Moderate, PS2_Very Strong, PM2_Supporting, PS3_Supporting, PP3, PM1. (Bayesian Points: 15; VCEP specifications version 1; 02/11/2022)
PreventionGenetics, part of Exact Sciences	RCV000851475	SCV000993762	pathogenic	not provided	2019-04-16	criteria provided, single submitter	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV001200976	SCV001371945	pathogenic	DICER1-related tumor predisposition	2019-07-01	criteria provided, single submitter	curation	ACMG criteria met: PS2, PS3, PM1, PM2, PP4
GeneDx	RCV000851475	SCV002013373	uncertain significance	not provided	2021-05-04	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27126690, 22187960, 26545620, 24481001, 26475046, 28177962, 29315962, 26983701, 26428316, 24136150, 27459524, 29037807, 28825729, 28323992, 26289771, 24909177, 24839956, 24675358, 26928971)
Ambry Genetics	RCV002345932	SCV002645594	pathogenic	Hereditary cancer-predisposing syndrome	2024-02-27	criteria provided, single submitter	clinical testing	The p.D1709N pathogenic mutation (also known as c.5125G>A), located in coding exon 23 of the DICER1 gene, results from a G to A substitution at nucleotide position 5125. The aspartic acid at codon 1709 is replaced by asparagine, an amino acid with highly similar properties. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported as a de novo occurrence with constitutional mosaicism in multiple individuals with DICER-1-related tumor predisposition syndrome (Brenneman M et al. F1000Res, 2015 Jul;4:214; de Kock L et al. J. Med. Genet., 2016 Jan;53:43-52). This variant resides in the metal ion-binding residue located in the RNase IIIb domain of the DICER1, that is defined as a mutational hotspot and critical functional domain (de Kock L et al. Hum Mutat, 2019 Nov;40:1939-1953). In multiple assays testing DICER1 function, this variant showed functionally abnormal results (Gurtan AM et al. RNA, 2012 Jun;18:1116-22; Heravi-Moussavi A et al. N Engl J Med, 2012 Jan;366:234-42; Wu MK et al. Endocr Relat Cancer, 2016 Feb;23:L1-5). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.