Submissions for variant NM_177438.3(DICER1):c.5096-12G>A

dbSNP: rs1566750865

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	RCV000703673	SCV002540809	pathogenic	DICER1-related tumor predisposition	2024-08-27	reviewed by expert panel	curation	The NM_177438.2:c.5096-12G>A variant in DICER1 is an intronic variant in intron 23. This variant received a total of 5 phenotype points across 6 unrelated probands meeting DICER1 VCEP phenotype specificity scoring criteria of >4 points (PS4; PMID:26289771, Internal lab contributors). 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, PMID:26289771). Sequencing of RNA from patients showed an out-of-frame impact on splicing, indicating that this variant impacts protein function (Internal lab data: GTR: 61756)(PS3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: (PS3, PS4, PP4, PM2_Supporting). (Bayesian Points: 10; VCEP specifications version 1.3; 08/27/2024).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000703673	SCV000832583	pathogenic	DICER1-related tumor predisposition	2024-12-08	criteria provided, single submitter	clinical testing	This sequence change falls in intron 23 of the DICER1 gene. It does not directly change the encoded amino acid sequence of the DICER1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with DICER1-related phenotypes (PMID: 26289771; External communication, internal data). ClinVar contains an entry for this variant (Variation ID: 580203). 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.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV001200968	SCV001371935	uncertain significance	not specified	2019-07-01	criteria provided, single submitter	curation	ACMG criteria met: PP3, PP4
Ambry Genetics	RCV002334372	SCV002642446	pathogenic	Hereditary cancer-predisposing syndrome	2024-04-16	criteria provided, single submitter	clinical testing	The c.5096-12G>A pathogenic mutation results from a G to A substitution 12 nucleotides before coding exon 23 in the DICER1 gene. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with DICER1-related disease (Ambry internal data; Schultz KA et al. Fam Cancer, 2016 Jan;15:105-10). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV003233829	SCV003931008	likely pathogenic	not provided	2022-12-02	criteria provided, single submitter	clinical testing	Functional studies from an outside lab demonstrate a damaging effect: abnormal splicing (External communication with Ambry Genetics); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 33922805, 28524158, 28654427, 29762508, 21501861, 26289771)