Submissions for variant NM_000548.5(TSC2):c.1458C>G (p.Asn486Lys)

dbSNP: rs200532154

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000190067	SCV000243742	likely benign	not specified	2015-10-26	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000644164	SCV000765854	uncertain significance	Tuberous sclerosis 2	2023-09-26	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 TSC2 protein function. ClinVar contains an entry for this variant (Variation ID: 41728). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. This variant is present in population databases (rs200532154, gnomAD 0.0009%). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 486 of the TSC2 protein (p.Asn486Lys).
CeGaT Center for Human Genetics Tuebingen	RCV000034645	SCV001961552	uncertain significance	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000644164	SCV002039548	uncertain significance	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390139	SCV002699905	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-15	criteria provided, single submitter	clinical testing	The p.N486K variant (also known as c.1458C>G), located in coding exon 14 of the TSC2 gene, results from a C to G substitution at nucleotide position 1458. The asparagine at codon 486 is replaced by lysine, an amino acid with similar properties. This variant was detected as a secondary finding in 1 out of 527 ClinSeq participants, unselected for personal or family history of cancer, who underwent exome sequencing; however, the clinical information for this particular individual was not provided (Johnston JJ et al. Am. J. Hum. Genet., 2012 Jul;91:97-108). This amino acid position is not 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.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034645	SCV000043528	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.