Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001049762 | SCV004015123 | uncertain significance | DICER1-related tumor predisposition | 2023-07-10 | reviewed by expert panel | curation | The NM_177438.2:c.5382G>C variant in DICER1 is a missense variant predicted to cause substitution of Glutamic Acid by Aspartic Acid at amino acid 1794 (p.Glu1794Asp). The highest population minor allele frequency in gnomAD v.2.1.1 (non-cancer) is 0.00005652 (1/17692 alleles) in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). This variant resides within the RNase IIIb domain of DICER1, a mutational hotspot domain with critical functionality as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID: 31342592). The computational predictor REVEL gives a score of 0.228, which is below the threshold of 0.5, and the splice site predictors MaxEntScan and SpliceAI indicate that the variant has no impact on splicing, evidence that does not predict a damaging effect on DICER1 function (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: PM1_supporting, BP4. (Bayesian Points: 0; VCEP specifications version 1.2.0; 07/10/2023). |
| Ambry Genetics | RCV001024012 | SCV001185963 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-11-26 | criteria provided, single submitter | clinical testing | The p.E1794D variant (also known as c.5382G>C), located in coding exon 24 of the DICER1 gene, results from a G to C substitution at nucleotide position 5382. The glutamic acid at codon 1794 is replaced by aspartic acid, 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. |
| Invitae | RCV001049762 | SCV001213832 | uncertain significance | DICER1-related tumor predisposition | 2022-10-05 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1794 of the DICER1 protein (p.Glu1794Asp). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 825692). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. This variant is present in population databases (rs766285402, gnomAD 0.006%). |
| Gene |
RCV002509592 | SCV002819078 | uncertain significance | not provided | 2022-07-05 | 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 |