ClinVar Miner

Submissions for variant NM_177438.3(DICER1):c.5438A>C (p.Glu1813Ala)

dbSNP: rs1889806272
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen RCV001201101 SCV002599119 uncertain significance DICER1-related tumor predisposition 2022-10-25 reviewed by expert panel curation The NM_177438.2:c.5438A>C variant in DICER1 is a missense variant predicted to cause substitution of Glutamic acid by Alanine at amino acid 1813 (p.Glu1813Ala). This variant is absent from gnomAD v2.1.1 and v3.1.1 (non-cancer) (PM2_Supporting). In vitro cleavage assay in ES cells showed that this variant fails to produce/reduces the capacity of the protein to produce 5p/3p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (PS3_Supporting; PMID: 23132766, 15242644, 17920623). The computational predictor REVEL gives a score of 0.949, which is above the threshold of 0.75, evidence that correlates with impact to DICER1 function (PP3). This variant resides in the p.E1813 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). This variant is a hotspot variant reported as a somatic finding in many individuals both with and without a separate germline DICER1 variant. This variant has been observed at low allele fraction in two probands with cancer diagnoses outside the recognized DICER1 spectrum (internal laboratory contributors). In summary, this variant meets the criteria to be classified as Variant of Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS3_Supporting, PM2_Supporting, PP3, PM1. (Bayesian Points: 5; VCEP specifications version 1.1.0; date of approval 10/25/2022) Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of recognized DICER1 phenotypes in individuals with the variant.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV001201101 SCV001372125 pathogenic DICER1-related tumor predisposition 2019-07-01 criteria provided, single submitter curation ACMG criteria met: PS3, PM1, PM2, PM7, PP3, PP4, BP1
Invitae RCV001201101 SCV002111602 uncertain significance DICER1-related tumor predisposition 2021-04-28 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 1813 of the DICER1 protein (p.Glu1813Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this variant affects DICER1 protein function (PMID: 15242644, 17920623). This variant has not been reported in the literature in the germline of individuals with DICER1-related conditions. ClinVar contains an entry for this variant (Variation ID: 933090). This variant is not present in population databases (ExAC no frequency).
Ambry Genetics RCV002348649 SCV002652244 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-08 criteria provided, single submitter clinical testing The p.E1813A variant (also known as c.5438A>C), located in coding exon 24 of the DICER1 gene, results from an A to C substitution at nucleotide position 5438. The glutamic acid at codon 1813 is replaced by alanine, an amino acid with dissimilar properties. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.