Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001208413 | SCV004231834 | uncertain significance | DICER1-related tumor predisposition | 2024-01-09 | reviewed by expert panel | curation | The NM_177438.2:c.4313A>G variant in DICER1 is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 1438 (p.Tyr1438Cys). 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: 0.2; MaxEntScan and SpliceAI: no effect on splicing) (BP4). 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. (Bayesian Points: 0; VCEP specifications version 1.2.0; 01/09/2024) |
| Invitae | RCV001208413 | SCV001379798 | uncertain significance | DICER1-related tumor predisposition | 2023-01-11 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 939082). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1438 of the DICER1 protein (p.Tyr1438Cys). 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 | RCV002327480 | SCV002633212 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-12-16 | criteria provided, single submitter | clinical testing | The p.Y1438C variant (also known as c.4313A>G), located in coding exon 22 of the DICER1 gene, results from an A to G substitution at nucleotide position 4313. The tyrosine at codon 1438 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is poorly 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. |
| Gene |
RCV002469352 | SCV002765508 | uncertain significance | not provided | 2022-06-16 | 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 |
| Baylor Genetics | RCV003469343 | SCV004193413 | uncertain significance | Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome | 2023-08-10 | criteria provided, single submitter | clinical testing |