Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
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, |
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. |