Submissions for variant NM_177438.3(DICER1):c.5123G>A (p.Gly1708Glu)

dbSNP: rs886037724

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota	RCV000240960	SCV000195630	pathogenic	DICER1-related tumor predisposition	2014-11-10	criteria provided, single submitter	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000240960	SCV001371943	likely pathogenic	DICER1-related tumor predisposition	2019-07-01	criteria provided, single submitter	curation	ACMG criteria met: PM1, PM2, PM7, PP3
Labcorp Genetics (formerly Invitae), Labcorp	RCV000240960	SCV003262527	likely pathogenic	DICER1-related tumor predisposition	2022-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1708 of the DICER1 protein (p.Gly1708Glu). 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. This variant disrupts the p.Gly1708 amino acid residue in DICER1. Other variant(s) that disrupt this residue have been observed in individuals with DICER1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 254345). This missense change has been observed in individual(s) with DICER1-related conditions (PMID: 26925222; Invitae). In at least one individual the data is consistent with this variant being in trans (on the opposite chromosome) from the pathogenic hotspot mutation p.Glu1813Gly in the individual's pleuropulmonary blastoma. This variant is not present in population databases (gnomAD no frequency).
Ambry Genetics	RCV003165680	SCV003860886	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-01-27	criteria provided, single submitter	clinical testing	The p.G1708E variant (also known as c.5123G>A), located in coding exon 23 of the DICER1 gene, results from a G to A substitution at nucleotide position 5123. The glycine at codon 1708 is replaced by glutamic acid, an amino acid with similar properties. This variant was detected in a patient with pleuropulmonary blastoma (PPB) (Brenneman M et al. F1000Res, 2015 Jul;4:214). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). Based on internal structural analysis, G1708E is more disruptive to the sensitive RNase IIIb domain than a nearby pathogenic variant (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.