Submissions for variant NM_177438.3(DICER1):c.2496G>C (p.Lys832Asn)

gnomAD frequency: 0.00001  dbSNP: rs769292296

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000340356	SCV000389756	likely benign	DICER1-related tumor predisposition	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Ambry Genetics	RCV001015750	SCV001176617	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-06	criteria provided, single submitter	clinical testing	The p.K832N variant (also known as c.2496G>C), located in coding exon 15 of the DICER1 gene, results from a G to C substitution at nucleotide position 2496. The lysine at codon 832 is replaced by asparagine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000340356	SCV001412884	uncertain significance	DICER1-related tumor predisposition	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 832 of the DICER1 protein (p.Lys832Asn). This variant is present in population databases (rs769292296, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. ClinVar contains an entry for this variant (Variation ID: 315109). 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 not expected to disrupt DICER1 protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237819	SCV002011610	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing