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| Gene | TSC1 |
| Variant | E636fs |
| Impact List | frameshift |
| Protein Effect | loss of function - predicted |
| Gene Variant Descriptions | TSC1 E636fs results in a change in the amino acid sequence of the Tsc1 protein beginning at aa 636 of 1164, likely resulting in premature truncation of the functional protein (UniProt.org). E636fs has not been characterized however, due to the effects of other truncation mutations downstream of E636 (PMID: 11875047, PMID: 20547222), is predicted to lead to a loss of Tsc1 protein function. |
| Associated Drug Resistance | |
| Category Variants Paths |
TSC1 mutant TSC1 inact mut TSC1 E636fs |
| Transcript | NM_000368.5 |
| gDNA | chr9:g.(132905672_132905673) |
| cDNA | c.(1906_1905) |
| Protein | p.E636fs |
| Source Database | RefSeq |
| Genome Build | GRCh38/hg38 |
| Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
|---|---|---|---|---|---|
| XM_017015099 | chr9:g.(132902727_132902728) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_000368 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001162426 | chr9:g.(132905669_132905670) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406595.1 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406609.1 | chr9:g.(132905669_132905670) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406610.1 | chr9:g.(132903800_132903801) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001162426.1 | chr9:g.(132905669_132905670) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001162426.2 | chr9:g.(132905669_132905670) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| XM_017015098 | chr9:g.(132905669_132905670) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406603.1 | chr9:g.(132905669_132905670) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406594.1 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406624.1 | chr9:g.(132902727_132902728) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| XM_011518979.3 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406606.1 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406599.1 | chr9:g.(132905669_132905670) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| XM_017015100.1 | chr9:g.(132902727_132902728) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| XM_005272211 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406592.1 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406605.1 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406614.1 | chr9:g.(132902727_132902728) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| XM_017015100 | chr9:g.(132902727_132902728) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406616.1 | chr9:g.(132902727_132902728) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| XM_006717271 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406597.1 | chr9:g.(132905669_132905670) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406598.1 | chr9:g.(132905669_132905670) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001162427.2 | chr9:g.(132903800_132903801) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| XM_017015097.1 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406617.1 | chr9:g.(132902727_132902728) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406619.1 | chr9:g.(132902727_132902728) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_000368.4 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| XM_017015096 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001162427.1 | chr9:g.(132903800_132903801) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001162427 | chr9:g.(132903800_132903801) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| XM_017015096.1 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406600.1 | chr9:g.(132905669_132905670) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_000368.5 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| XM_006717271.1 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406601.1 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| XM_017015097 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406615.1 | chr9:g.(132902727_132902728) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| XM_005272211.1 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406604.1 | chr9:g.(132905669_132905670) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| XM_017015099.1 | chr9:g.(132902727_132902728) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406608.1 | chr9:g.(132905669_132905670) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| XM_017015098.1 | chr9:g.(132905669_132905670) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406630.1 | chr9:g.(132897200_132897201) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406602.1 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001362177.2 | chr9:g.(132902727_132902728) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406629.1 | chr9:g.(132897200_132897201) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406593.1 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406596.1 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| XM_011518979 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406607.1 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| XM_011518979.2 | chr9:g.(132905672_132905673) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| NM_001406618.1 | chr9:g.(132902727_132902728) | c.(1906_1905) | p.E636fs | RefSeq | GRCh38/hg38 |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| TSC1 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 |
| TSC1 inact mut | clear cell renal cell carcinoma | not applicable | N/A | Guideline | Risk Factor | Germline inactivating mutations in TSC1 result in tuberous sclerosis complex (TSC), which is associated with increased risk of developing clear cell renal cell carcinoma (NCCN.org). | detail... |
| TSC1 inact mut | islet cell tumor | not applicable | N/A | Guideline | Risk Factor | Germline inactivating mutations in TSC1 result in tuberous sclerosis complex (TSC), which is associated with increased risk of developing pancreatic neuroendocrine tumors (NCCN.org). | detail... |
| TSC1 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 |
| TSC1 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 |
| TSC1 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 |
| TSC1 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... |
| TSC1 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 |
| TSC1 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... |
| TSC1 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 |
| TSC1 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 |
| TSC1 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 |
| TSC1 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 |
| TSC1 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 |
| TSC1 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 |
| TSC1 mutant | bladder carcinoma | sensitive | Everolimus | Phase II | Actionable | A retrospective study of a Phase II trial correlated increased sensitivity to the mTOR inhibitor Afinitor (everolimus) with TSC1 mutations in bladder cancer patients (PMID: 22923433). | 22923433 |