Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002336158 | SCV002642845 | uncertain significance | Hereditary cancer-predisposing syndrome | 2017-09-01 | criteria provided, single submitter | clinical testing | The p.Y1650C variant (also known as c.4949A>G), located in coding exon 37 of the TSC2 gene, results from an A to G substitution at nucleotide position 4949. The tyrosine at codon 1650 is replaced by cysteine, an amino acid with highly dissimilar properties. In one study, this alteration was detected in an individual who met diagnostic criteria for tuberous sclerosis (TSC) (Beauchamp RL et al. Hum. Mutat., 1998;12:408-16). 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. |
| Tuberous sclerosis database |
RCV000042594 | SCV000066388 | not provided | Tuberous sclerosis syndrome | no assertion provided | curation | ||
| Division of Hematology/Oncology, |
RCV000590964 | SCV000693714 | drug response | Everolimus response | 2017-01-01 | no assertion criteria provided | clinical testing | Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR) pathway, is currently approved for treatment of advanced renal-cell carcinoma (RCC) after failure of initial treatment with the tyrosine kinase inhibitors. Patients with tuberous sclerosis complex (TSC) syndrome can also develop RCC primarily mediated through mTOR signaling. However, the efficacy and duration of response of mTOR inhibition in patients with TSC-associated RCC is not well known. Herein, we describe a case of a patient with TSC2-associated metastatic RCC with mutations H1620R and Y1650C who has had an exceptional response to everolimus in the frontline setting and continues to derive benefit from mTOR inhibition 2 yr into therapy. Furthermore, the alteration H1620R in exon 37 resulting in a missense mutation is likely deleterious given our findings and previous analyses of the TSC2 gene. Further studies of somatic mutations in extended responders to mTOR inhibitors will help personalize therapy for these patients. It also emphasizes the value of targeted therapies based on genomic analyses. |