Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000549329 | SCV004032137 | uncertain significance | DICER1-related tumor predisposition | 2023-08-22 | reviewed by expert panel | curation | The NM_177438.2:c.5257G>A variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 1753 (p.Asp1753Asn). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer (PM2_Supporting). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.431; MaxEntScan and SpliceAI: no effect on splicing (BP4). This variant resides within the RNase IIIb mutational hotspot domain with critical functionality as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID: 31342592). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; GTR ID: 500031, 61756). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM2_Supporting, BP4, PM1_Supporting, BS2_Supporting. (Bayesian Points: 0; VCEP specifications version 1.2.0; 08/22/23) |
| Labcorp Genetics |
RCV000549329 | SCV000658338 | uncertain significance | DICER1-related tumor predisposition | 2024-10-12 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1753 of the DICER1 protein (p.Asp1753Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. ClinVar contains an entry for this variant (Variation ID: 477251). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DICER1 protein function with a negative predictive value of 95%. 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. |
| Ambry Genetics | RCV001023806 | SCV001185729 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-09-02 | criteria provided, single submitter | clinical testing | The p.D1753N variant (also known as c.5257G>A), located in coding exon 23 of the DICER1 gene, results from a G to A substitution at nucleotide position 5257. The aspartic acid at codon 1753 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV003478195 | SCV004221861 | uncertain significance | not provided | 2023-07-21 | criteria provided, single submitter | clinical testing | This variant has not been reported in the published literature. It also has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. |
| Baylor Genetics | RCV004569083 | SCV005059553 | uncertain significance | Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome | 2023-11-14 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV003478195 | SCV005327348 | uncertain significance | not provided | 2024-02-25 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge |