Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001052273 | SCV001216475 | uncertain significance | Tuberous sclerosis 2 | 2024-01-18 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 1528 of the TSC2 protein (p.Glu1528Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 848503). 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 with a negative predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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. |
| Ambry Genetics | RCV002339262 | SCV002638580 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-11-30 | criteria provided, single submitter | clinical testing | The p.E1528Q variant (also known as c.4582G>C), located in coding exon 35 of the TSC2 gene, results from a G to C substitution at nucleotide position 4582. The glutamic acid at codon 1528 is replaced by glutamine, an amino acid with highly similar properties. In one study, this alteration was identified in a female diagnosed with bilateral breast cancer who also carried an ATM exon 62–63 deletion (Penkert J et al. Breast Cancer Res, 2018 08;20:87). 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. |
| Gene |
RCV003156307 | SCV003845717 | uncertain significance | not provided | 2022-09-21 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. |