Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001319972 | SCV005686357 | uncertain significance | DICER1-related tumor predisposition | 2025-01-07 | reviewed by expert panel | curation | The NM_177438.3:c.2051T>C variant in DICER1 is a missense variant predicted to cause substitution of methionine by threonine at amino acid 684 (p.Met684Thr). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.000001863 (3/1609982 alleles) with a highest population minor allele frequency of 0.00002672 (2/74840 alleles) in the African/African American population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.345; 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: BP4. (Bayesian Points: -1; VCEP specifications version 1.3.0; 01/07/2025) |
| Ambry Genetics | RCV000567909 | SCV000661982 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-06-12 | criteria provided, single submitter | clinical testing | The p.M684T variant (also known as c.2051T>C), located in coding exon 12 of the DICER1 gene, results from a T to C substitution at nucleotide position 2051. The methionine at codon 684 is replaced by threonine, an amino acid with similar properties. This amino acid position is 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 |
RCV001319972 | SCV001510739 | uncertain significance | DICER1-related tumor predisposition | 2024-10-21 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 684 of the DICER1 protein (p.Met684Thr). This variant is present in population databases (no rsID available, gnomAD 0.02%). 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: 479642). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DICER1 protein function. 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. |
| Gene |
RCV003231533 | SCV003929828 | uncertain significance | not provided | 2022-12-02 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge |