ClinVar Miner

Submissions for variant NM_177438.3(DICER1):c.4050+1G>A

dbSNP: rs875989783
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000211099 SCV000267167 pathogenic Pineoblastoma 2014-07-15 criteria provided, single submitter research
Ambry Genetics RCV000493490 SCV000581553 likely pathogenic Hereditary cancer-predisposing syndrome 2013-09-23 criteria provided, single submitter clinical testing ​The c.4050+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 20 of the DICER1 gene. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project.To date, this alteration has been detected with an allele frequency of approximately 0.39% (greater than 250 alleles tested) in our clinical cohort (includes this individual). Based on nucleotide sequence alignment, this position is completely conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice donor site are typically deleterious in nature (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). As such, the c.4050+1G>A variant is classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences RCV000851414 SCV000993695 likely pathogenic not provided 2014-04-17 criteria provided, single submitter clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV001201079 SCV001372092 pathogenic DICER1-related tumor predisposition 2019-07-01 criteria provided, single submitter curation ACMG criteria met: PVS1, PM2, PP4
Labcorp Genetics (formerly Invitae), Labcorp RCV001201079 SCV002238862 pathogenic DICER1-related tumor predisposition 2022-10-04 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 21 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). Disruption of this splice site has been observed in individuals with DICER1-related conditions (PMID: 21882293, 25022261). ClinVar contains an entry for this variant (Variation ID: 225887). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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