ClinVar Miner

Submissions for variant NM_177438.3(DICER1):c.2257-2A>G

dbSNP: rs2140034081
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen RCV003774730 SCV005043097 uncertain significance DICER1-related tumor predisposition 2024-02-27 reviewed by expert panel curation The NM_177438.2:c.2257-2A>G variant in DICER1 occurs within the canonical splice acceptor site of intron 14. It is predicted to cause skipping of biologically-relevant exon 15/27, resulting in an in-frame deletion, removing <10% of the protein (PVS1_Moderate). 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; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 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: PS4_Supporting, PM2_Supporting, and PVS1_Moderate. (Bayesian Points: 4; VCEP specifications version 1.3.0; 02/27/2024)
3billion, Medical Genetics RCV002250920 SCV002521129 likely pathogenic Euthyroid goiter 2022-05-22 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp RCV003774730 SCV004694035 likely pathogenic DICER1-related tumor predisposition 2022-11-13 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 14 of the DICER1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DICER1 are known to be pathogenic (PMID: 19556464, 21266384). This variant is not present in population databases (gnomAD no frequency). 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: 1687238). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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