Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001201061 | SCV004231826 | likely pathogenic | DICER1-related tumor predisposition | 2024-01-09 | reviewed by expert panel | curation | The NM_177438.2:c.2516C>T variant in DICER1 is a missense variant predicted to cause substitution of serine by phenylalanine at amino acid 839 (p.Ser839Phe). This variant received a total of 1 phenotype point across 2 unrelated probands meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMIDs: 3799599, 21205968; Internal Contributors: Guy's and St Thomas’ NHS Foundation Trust). All reported phenotypes to date have been thyroid phenotypes (multi-nodular goiter and thyroid cancer, including pediatric). At least one patient with this variant was found to have a somatic second hit in a recognized DICER1 hotspot codon on tumor sequencing, which is highly specific for DICER1-related tumor predisposition (PP4, PMIDs: 27459524, 26033159). The variant has been reported to segregate with multi-nodular goiter in 20 affected family members from 1 family (PP1_Moderate; PMIDs: 2120596). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting). In vitro cleavage assay carried out using immunopurified DICER1 variant Ser839Phe showed that this variant reduces the capacity of the protein to produce 5p/3p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (PS3_Supporting; Wu, McGill 2018; Torrez, University of Michigan 2023, PMID: 37333613). The computational predictor REVEL gives a score of 0.519, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function (PP3 and BP4 not met). In summary, this variant meets the criteria to be classified as Likely Pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PP4, PP1_Moderate, PM2_Supporting, PS3_Supporting. (Bayesian Points: 6; VCEP specifications version 1.2.0; 01/09/2024) |
| Foulkes Cancer Genetics LDI, |
RCV001201061 | SCV001372067 | likely pathogenic | DICER1-related tumor predisposition | 2019-07-01 | criteria provided, single submitter | curation | ACMG criteria met: PS3, PM2, PP1, PP3, BP1 |
| Ambry Genetics | RCV002426517 | SCV002744360 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-04-02 | criteria provided, single submitter | clinical testing | The p.S839F variant (also known as c.2516C>T), located in coding exon 15 of the DICER1 gene, results from a C to T substitution at nucleotide position 2516. The serine at codon 839 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant has been identified in family with non toxic multi-nodular goiter (Rio Frio T et al. JAMA, 2011 Jan;305:68-77). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV001201061 | SCV004297168 | pathogenic | DICER1-related tumor predisposition | 2023-08-30 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 839 of the DICER1 protein (p.Ser839Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with DICER1 syndrome (PMID: 21205968). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30566). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DICER1 protein function. For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000023526 | SCV000044817 | pathogenic | Euthyroid goiter | 2011-01-05 | no assertion criteria provided | literature only |