Submissions for variant NM_177438.3(DICER1):c.5527+3A>G

dbSNP: rs1595313951

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	RCV003127586	SCV003803736	likely pathogenic	DICER1-related tumor predisposition	2023-02-03	reviewed by expert panel	curation	The NM_177438.2:c.5527+3A>G variant in DICER1 is an intronic variant resulting from a A to G substitution 3 nucleotides downstream from coding exon 25. This variant received a total of 1 phenotype points across 1 proband meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; Internal contributor GTR: 500086). 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 syndrome (PP4, PMID: 24481001, Internal contributor GTR: 500086). This variant is absent from gnomAD v2.1.1 and v3.1.1 (non-cancer) (PM2_Supporting). Sequencing of RNA from patients showed an out-of-frame impact on splicing, indicating that this variant impacts protein function (PS3; Internal lab contributor GTR: 500086). The splice site predictors MaxEntScan and SpliceAI indicate that the variant impacts splicing, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PP4, PM2_Supporting, PP3, PS3. (Bayesian Points: 8; VCEP specifications version 1.1.0; 02/03/2023)
Ambry Genetics	RCV001024224	SCV001186206	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-15	criteria provided, single submitter	clinical testing	The c.5527+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 24 in the DICER1 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV002295324	SCV001372208	likely pathogenic	Pleuropulmonary blastoma	2022-11-04	criteria provided, single submitter	curation	This variant meets the criteria to be classified as Likely Pathogenic for DICER1 syndrome based on the ACMG/AMP criteria and ClinGen DICER1 guidelines: PS3, PS4_Moderate, PM2_Supporting, PP3, PP4.