Submissions for variant NM_177438.3(DICER1):c.5438A>C (p.Glu1813Ala)

dbSNP: rs1889806272

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	RCV001201101	SCV002599119	uncertain significance	DICER1-related tumor predisposition	2025-01-07	reviewed by expert panel	curation	The NM_177438.2:c.5438A>C variant in DICER1 is a missense variant predicted to cause substitution of Glutamic acid by Alanine at amino acid 1813 (p.Glu1813Ala). Although this variant has been observed in low variant allele fraction cases, to our knowledge, this variant has not been reported in individuals with DICER1-related tumor predisposition (PS4 not met; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro cleavage assay carried out using immunopurified DICER1 variant Glu1813Ala showed that this variant reduces the capacity of the protein to produce 5p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (PS3_Supporting; PMID: 15242644, 17920623, 23132766). In silico tools predict damaging impact of the variant on protein function (REVEL: 0.949) (PP3). This variant resides in the p.E1813 metal ion-binding residue located in the RNase IIIb domain of DICER1, that is defined as a mutational hotspot and critical functional domain by the ClinGen DICER1 VCEP (PM1; PMID: 31342592). This variant is a hotspot variant reported as a somatic finding in many individuals both with and without a separate germline DICER1 variant. This variant has been observed at low allele fraction in two probands with cancer diagnoses outside the recognized DICER1 spectrum (Internal laboratory contributors). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS3_Supporting, PM2_Supporting, PP3, PM1. (Bayesian Points: 5; VCEP specifications version 1.3.0; 01/07/2025). Although available evidence supports germline pathogenicity of recurrent DICER1 somatic hotspot variants (PMID: 26925222), the clinical significance of this variant in the germline remains uncertain at this time since it has not yet been observed in the germline of an individual with a recognized DICER1 phenotype.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV001201101	SCV001372125	pathogenic	DICER1-related tumor predisposition	2019-07-01	criteria provided, single submitter	curation	ACMG criteria met: PS3, PM1, PM2, PM7, PP3, PP4, BP1
Labcorp Genetics (formerly Invitae), Labcorp	RCV001201101	SCV002111602	uncertain significance	DICER1-related tumor predisposition	2021-04-28	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 sequence change replaces glutamic acid with alanine at codon 1813 of the DICER1 protein (p.Glu1813Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in the germline of individuals with DICER1-related conditions. ClinVar contains an entry for this variant (Variation ID: 933090). Experimental studies have shown that this variant affects DICER1 protein function (PMID: 15242644, 17920623).
Ambry Genetics	RCV002348649	SCV002652244	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-08	criteria provided, single submitter	clinical testing	The p.E1813A variant (also known as c.5438A>C), located in coding exon 24 of the DICER1 gene, results from an A to C substitution at nucleotide position 5438. The glutamic acid at codon 1813 is replaced by alanine, an amino acid with dissimilar properties. 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.