Submissions for variant NM_177438.3(DICER1):c.5126A>G (p.Asp1709Gly)

dbSNP: rs1555366979

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000546662	SCV000658329	uncertain significance	DICER1-related tumor predisposition	2023-07-20	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Asp1709 amino acid residue in DICER1, a functionally conserved metal-binding residue within the RNase IIIb domain (PMID: 22187960, 26408257, 23132766). Other variants that disrupt this residue have been reported in individuals with DICER1-related conditions (PMID: 22187960, 26475046, 24839956, 24676357). This suggests that this residue is clinically significant, and that variants that disrupt this residue may be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DICER1 protein function. ClinVar contains an entry for this variant (Variation ID: 477242). This variant has been reported as mosaic in an individual with pleuropulmonary blastoma (PMID: 26925222). This variant also has been reported as a somatic variant in DICER1-related tumors (PMID: 22187960, 26555935, 27459524). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1709 of the DICER1 protein (p.Asp1709Gly).
Ambry Genetics	RCV001023581	SCV001185481	uncertain significance	Hereditary cancer-predisposing syndrome	2019-11-21	criteria provided, single submitter	clinical testing	The p.D1709G variant (also known as c.5126A>G), located in coding exon 23 of the DICER1 gene, results from an A to G substitution at nucleotide position 5126. The aspartic acid at codon 1709 is replaced by glycine, an amino acid with similar properties. In a study of 124 children with pleuropulmonary blastoma, this variant was reported as a germline mosaic finding in one patient, who had small intestinal polyps, pleuropulmonary blastoma, and cystic nephroma (Brenneman M et al. F1000Res. 2015 Jul;4:214). This variant has been reported as a somatic finding in many studies, including studies of ovarian sex cord stromal tumors and multinodular goiters (de Kock L et al. Hum. Mutat. 2019 11;40:1939-1953). This alteration is located in the RNase IIIb domain of the DICER1 protein and variants at this codon have been characterized as somatic hotspot mutations (Foulkes WD et al. Nat. Rev. Cancer. 2014 Oct;14:662-72). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	RCV000546662	SCV001371948	pathogenic	DICER1-related tumor predisposition	2019-07-01	criteria provided, single submitter	curation	ACMG criteria met: PS2, PS3, PM1, PM2, PP4