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| Gene | TSC2 |
| Variant | S1045F |
| Impact List | missense |
| Protein Effect | loss of function - predicted |
| Gene Variant Descriptions | TSC2 S1045F does not lie within any known functional domains of the Tsc2 protein (UniProt.org). S1045F retains the ability to form TSC complex, but results in reduced ability to inhibit S6k phosphorylation in culture (PMID: 31799751), and therefore, is predicted to lead to a loss of Tsc2 protein function. |
| Associated Drug Resistance | |
| Category Variants Paths |
TSC2 mutant TSC2 inact mut TSC2 S1045F |
| Transcript | NM_000548.5 |
| gDNA | chr16:g.2079278C>T |
| cDNA | c.3134C>T |
| Protein | p.S1045F |
| Source Database | RefSeq |
| Genome Build | GRCh38/hg38 |
| Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
|---|---|---|---|---|---|
| NM_001406676.1 | chr16:g.2079427_2079428delAGinsTT | c.3133_3134delAGinsTT | p.S1045F | RefSeq | GRCh38/hg38 |
| NM_001406675.1 | chr16:g.2079425_2079426delCGinsTT | c.3134_3135delCGinsTT | p.S1045F | RefSeq | GRCh38/hg38 |
| NM_001114382 | chr16:g.2079278C>T | c.3134C>T | p.S1045F | RefSeq | GRCh38/hg38 |
| NM_000548.4 | chr16:g.2079278C>T | c.3134C>T | p.S1045F | RefSeq | GRCh38/hg38 |
| XM_011522636.2 | chr16:g.2079278C>T | c.3134C>T | p.S1045F | RefSeq | GRCh38/hg38 |
| XM_011522636 | chr16:g.2079278C>T | c.3134C>T | p.S1045F | RefSeq | GRCh38/hg38 |
| NM_000548.5 | chr16:g.2079278C>T | c.3134C>T | p.S1045F | RefSeq | GRCh38/hg38 |
| NM_001114382.2 | chr16:g.2079278C>T | c.3134C>T | p.S1045F | RefSeq | GRCh38/hg38 |
| NM_001114382.3 | chr16:g.2079278C>T | c.3134C>T | p.S1045F | RefSeq | GRCh38/hg38 |
| XM_011522636.3 | chr16:g.2079278C>T | c.3134C>T | p.S1045F | RefSeq | GRCh38/hg38 |
| NM_000548 | chr16:g.2079278C>T | c.3134C>T | p.S1045F | RefSeq | GRCh38/hg38 |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| TSC2 inact mut | Advanced Solid Tumor | predicted - sensitive | Nab-rapamycin | Clinical Study | Actionable | In a clinical study, Fyarro (nab-rapamycin) treatment in patients with advanced solid tumors harboring mutations in TSC1 or TSC2 led to a partial response in 4 patients, stable disease in 2 patients and progressive disease in 1 patient of 7 enrolled patients (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 3111-3111; NCT03817515). | detail... |
| TSC2 inact mut | Advanced Solid Tumor | no benefit | Everolimus | Phase II | Actionable | In a Phase II trial, Afinitor (everolimus) treatment resulted in limited activity with an objective response rate of 7% (2/30, 2 partial responses), stable disease in an additional 40% (12/30), a clinical benefit rate of 13% (4/30), a median progression-free survival of 2.3 months, and a median overall survival of 7.3 months in patients with advanced solid tumors harboring inactivating TSC1 or TSC2 mutations or activating MTOR mutations (PMID: 33727259; NCT02201212). | 33727259 |
| TSC2 inact mut | transitional cell carcinoma | no benefit | Sapanisertib | Phase II | Actionable | In a Phase II trial, treatment with Sapanisertib (MLN0128) in metastatic urothelial carcinoma patients with either a TSC1 or TSC2 activating mutation (n=13) did not result in an objective response and led to a median overall survival of 3.4 months, and the trial was terminated early due to limited clinical activity and poor drug tolerability (Journal of Clinical Oncology 39, no. 6_suppl (February 20, 2021) 431-431; NCT03047213). | detail... |
| TSC2 inact mut | renal cell carcinoma | predicted - sensitive | Everolimus | Clinical Study - Cohort | Actionable | In a retrospective analysis, 28% (12/43) of metastatic renal cell carcinoma patients who responded to rapalogs, Afinitor (everolimus) or Torisel (temsirolimus), harbored inactivating TSC1, TSC2 mutations and/or activating MTOR mutations, compared to 11% (4/36) in patients who did not respond to therapy (PMID: 26831717). | 26831717 |
| TSC2 inact mut | islet cell tumor | not applicable | N/A | Guideline | Risk Factor | Germline inactivating mutations in TSC2 result in tuberous sclerosis complex (TSC), which is associated with increased risk of developing pancreatic neuroendocrine tumors (NCCN.org). | detail... |
| TSC2 inact mut | castration-resistant prostate carcinoma | predicted - sensitive | CC-115 + Enzalutamide | Phase I | Actionable | In a Phase Ib trial, Xtandi (enzalutamide) plus CC-115 was safe and led to a PSA reduction >= 50% (PSA50) in 80% (32/40) and >=90% (PSA90) in 58% (23/40) of metastatic castration-resistant prostate cancer patients at 12 weeks, and patients with PIK3CA activating mutations or PTEN or TSC1/2 loss of function (n=16) achieved a PSA50, PSA90, and median radiographic progression-free survival of 94%, 63%, and 19.6 mo vs 67%, 47%, and 22.1 mo in PI3K pathway wild-type patients (n=15) (PMID: 37980367; NCT02833883). | 37980367 |
| TSC2 inact mut | perivascular epithelioid cell tumor | predicted - sensitive | Nab-rapamycin | Phase II | Actionable | In a Phase II trial (AMPECT), Fyarro (nab-rapamycin) treatment in patients with perivascular epithelioid cell tumors (PEComas) resulted in partial response in 20% (1/5) of patients with TSC1 mutations, 89% (8/9) of patients with TSC2 mutations, and 9% (1/11) of patients without a TSC1 or TSC2 mutation (PMID: 34637337; NCT02494570). | 34637337 |
| TSC2 inact mut | renal cell carcinoma | predicted - sensitive | Temsirolimus | Clinical Study - Cohort | Actionable | In a retrospective analysis, 28% (12/43) of metastatic renal cell carcinoma patients who responded to rapalogs, Afinitor (everolimus) or Torisel (temsirolimus), harbored inactivating TSC1, TSC2 mutations and/or activating MTOR mutations, compared to 11% (4/36) in patients who did not respond to therapy (PMID: 26831717). | 26831717 |
| TSC2 inact mut | clear cell renal cell carcinoma | not applicable | N/A | Guideline | Risk Factor | Germline inactivating mutations in TSC2 result in tuberous sclerosis complex (TSC), which is associated with increased risk of developing clear cell renal cell carcinoma (NCCN.org). | detail... |
| TSC2 mutant | lung non-small cell carcinoma | no benefit | Vistusertib | Case Reports/Case Series | Actionable | In a Phase II trial (NLMT), Vistusertib (AZD2014) treatment did not result in a confirmed response (0/5) or durable clinical benefit (0/5) in patients with non-small cell lung cancer harboring TSC1 or TSC2 mutations, thus the cohort was closed due to futility (PMID: 32669708, NCT02664935). | 32669708 |
| TSC2 mutant | osteosarcoma | no benefit | Temsirolimus | Preclinical - Pdx | Actionable | In a preclinical study, Torisel (temsirolimus) treatment did not improve event-free survival in an osteosarcoma patient-derived xenograft (PDX) model harboring a TSC2 mutation (PMID: 37523146). | 37523146 |
| TSC2 mutant | renal cell carcinoma | conflicting | Everolimus | Clinical Study - Cohort | Actionable | In a retrospective analysis, TSC1, TSC2, or MTOR mutation status was not associated with progression-free survival in renal cell carcinoma patients treated with Afinitor (everolimus) (PMID: 30327302). | 30327302 |
| TSC2 mutant | renal cell carcinoma | conflicting | Everolimus | Case Reports/Case Series | Actionable | In a clinical study, treatment with Afinitor (everolimus) or Torisel (temsirolimus) resulted in more partial responses (odds ratio = 0.08, p=0.030) in patients with renal cell carcinoma harboring mTOR pathway mutations, including MTOR (n=8), TSC1 (n=1), and TSC2 (n=2), than those without mutations (n=76) (PMID: 31335987). | 31335987 |
| TSC2 mutant | subependymal giant cell astrocytoma | predicted - sensitive | Everolimus | Phase III | Actionable | In a Phase III trial (EXIST-1), Afinitor (everolimus) treatment resulted in a 50% or more tumor reduction in 35% (27/78) of adult and pediatric patients diagnosed with tuberous sclerosis complex and had subependymal giant cell astrocytoma, compared to 0% (0/39) in the placebo group, 85% (99/117) of the patients harbored mutations in TSC1 and/or TSC2 (PMID: 23158522; NCT00789828). | 23158522 |
| TSC2 mutant | osteosarcoma | no benefit | Irinotecan + Temozolomide + Temsirolimus | Case Reports/Case Series | Actionable | In a clinical case study, Torisel (temsirolimus), Temodar (temozolomide), and Camptosar (irinotecan) combination treatment resulted in progressive disease in a pediatric patient with osteosarcoma harboring a TSC2 mutation (PMID: 37523146; NCT03336931). | 37523146 |
| TSC2 mutant | hepatocellular carcinoma | decreased response | Sorafenib | Clinical Study - Cohort | Actionable | In a clinical case study, Nexavar (sorafenib) treatment of patients with hepatocellular carcinoma harboring Mtor pathway mutations in PIK3CA, PTEN, TSC2, or TSC1 (n=12), resulted in a lower disease control rate (8.3% vs. 40.2%), shorter progression-free survival (1.9 months vs. 5.3 months) and shorter overall survival (10.4 months vs. 17.9 months) compared to patients without mutations in this pathway (n=67) (PMID: 30373752; NCT01775072). | 30373752 |
| TSC2 mutant | renal cell carcinoma | predicted - sensitive | Temsirolimus | Case Reports/Case Series | Actionable | In a clinical study, treatment with Afinitor (everolimus) or Torisel (temsirolimus) resulted in more partial responses (odds ratio = 0.08, p=0.030) in patients with renal cell carcinoma harboring mTOR pathway mutations, including MTOR (n=8), TSC1 (n=1), and TSC2 (n=2), than those without mutations (n=76) (PMID: 31335987). | 31335987 |