Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001233207 | SCV002540837 | likely benign | DICER1-related tumor predisposition | 2022-05-18 | reviewed by expert panel | curation | The NM_177438.2:c.1907+3A>T variant in DICER1 is an intronic variant located in exon 11. The results from 2 in silico splicing predictors [MaxEntScan, SpliceAI] do not agree, supporting neither a deleterious nor benign impact on splicing. The variant is absent from gnomAD v2.1.1 and v3.1.1 (non-cancer) (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in any individuals with DICER1 syndrome. Sequencing of RNA from 3 patients showed that this variant does not affect splicing, indicating that this variant is unlikely to impact protein function (BS3; Internal contributor GTR: 61756). In summary, this variant meets the criteria to be classified as LIKELY BENIGN for DICER1 syndrome. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS3, PM2_Supporting. (Bayesian Points: -3; VCEP specifications version 1; 02/11/2022) |
Ambry Genetics | RCV001013582 | SCV001174189 | likely benign | Hereditary cancer-predisposing syndrome | 2020-01-07 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
Invitae | RCV001233207 | SCV001405790 | uncertain significance | DICER1-related tumor predisposition | 2020-02-06 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 11 of the DICER1 gene. It does not directly change the encoded amino acid sequence of the DICER1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DICER1-related conditions. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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. |