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Gene Symbol TSC1
Synonyms LAM | TSC
Gene Description TSC1, TSC complex subunit 1, is a tumor suppressor (PMID: 30562755) that forms a complex with Tsc2 and inhibits mTOR pathway signaling, thus regulating cell growth and metabolism (PMID: 27226234). Germline TSC1 inactivating mutations cause tuberous sclerosis complex and somatic TSC1 mutations have been identified in various cancers, including renal cell carcinoma, mucosal melanoma, and breast cancer (PMID: 27226234, PMID: 30327302, PMID: 29185092, PMID: 28027327).
ACMG Incidental List v3.0:
Yes, Tuberous sclerosis complex (PMID: 34012068)
NCBI Gene ID Chromosome Map Location Canonical Transcript Gene Role
7248 9 9q34.13 NM_000368 Tumor suppressor (PMID: 30606230)

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TSC1 E636fs bladder carcinoma sensitive Everolimus Case Reports/Case Series 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, including one patient harboring TSC1 E636fs* who had a durable complete response (PMID: 22923433). 22923433
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
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 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 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 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 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 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 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 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 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 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 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 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 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 loss urinary bladder cancer sensitive Sirolimus Preclinical Actionable In a preclinical study, Rapamune (sirolimus) inhibited proliferation of cultured bladder cancer cells lacking TSC1 (PMID: 23401075). 23401075
TSC1 loss urinary bladder cancer sensitive Torin 1 Preclinical Actionable In a preclinical study, Torin 1 inhibited proliferation of cultured bladder cancer cells lacking TSC1 (PMID: 23401075). 23401075
TSC1 loss urinary bladder cancer sensitive Luminespib + Sirolimus Preclinical Actionable In a preclinical study, Luminespib (AUY922), in combination with Rapamune (sirolimus), inhibited growth of bladder cancer cells lacking TSC1 to a greater extent than either therapy alone (PMID: 23401075). 23401075
TSC1 loss urinary bladder cancer sensitive Luminespib + Torin 1 Preclinical Actionable In a preclinical study, Luminespib (AUY922), in combination with Torin 1 inhibited growth of bladder cancer cells lacking TSC1 to a greater extent than either therapy alone (PMID: 23401075). 23401075
TSC1 Q516* transitional cell carcinoma no benefit Buparlisib Case Reports/Case Series Actionable In a Phase II trial, Buparlisib (BKM120) treatment resulted in progressive disease in a patient with metastatic urothelial carcinoma harboring TSC1 Q516* (PMID: 32767682; NCT01551030). 32767682
TSC1 del urinary bladder cancer sensitive Metformin Preclinical Actionable In a preclinical study, bladder cancer cells harboring a deletion of TSC1 were sensitive to Glucophage (metformin) in culture, resulting in cell growth inhibition (PMID: 26921394). 26921394
PIK3CA act mut TSC1 del estrogen-receptor positive breast cancer resistant Alpelisib Preclinical - Cell culture Actionable In a preclinical study, PIK3CA-mutant, ESR1 (ER)-positive breast cancer cells with knockout of TSC1 demonstrated resistance to growth inhibition by Piqray (alpelisib) in culture, and decreased sensitivity to Piqray (alpelisib) in a cell line xenograft model (PMID: 33685991). 33685991
PIK3CA act mut TSC1 del estrogen-receptor positive breast cancer resistant Taselisib Preclinical - Cell culture Actionable In a preclinical study, PIK3CA-mutant, ESR1 (ER)-positive breast cancer cell lines with knockout of TSC1 were resistant to treatment with Taselisib (GDC-0032) in culture (PMID: 33685991). 33685991
TSC1 M271T TSC2 L604P endometrial cancer sensitive Miransertib Preclinical - Pdx Actionable In a preclinical study, a patient-derived xenograft (PDX) model of endometrial cancer harboring TSC1 M271T and TSC2 L604P was sensitive to Miransertib (ARQ092), demonstrating greater than 90% inhibition of tumor growth (PMID: 26469692). 26469692
TSC1 S331Efs*10 TSC1 LOH transitional cell carcinoma predicted - sensitive Buparlisib Case Reports/Case Series Actionable In a Phase II trial, Buparlisib (BKM120) treatment resulted in stable disease in a patient with metastatic urothelial carcinoma harboring TSC1 S331Efs*10 and TSC1 loss of heterozygosity (PMID: 32767682; NCT01551030). 32767682
TSC1 R98* hepatocellular carcinoma predicted - sensitive Everolimus Case Reports/Case Series Actionable In a clinical study, a hepatocellular carcinoma patient harboring TSC1 R98* achieved stable disease following treatment with Afinitor (everolimus) (PMID: 30373752). 30373752
TSC1 R500* TSC1 LOH transitional cell carcinoma predicted - sensitive Buparlisib Case Reports/Case Series Actionable In a Phase II trial, Buparlisib (BKM120) treatment resulted in a partial response in a patient with metastatic urothelial carcinoma harboring TSC1 R500* and TSC1 loss of heterozygosity (PMID: 32767682; NCT01551030). 32767682
PIK3CA amp TSC1 LOH transitional cell carcinoma predicted - sensitive Buparlisib Case Reports/Case Series Actionable In a Phase II trial, Buparlisib (BKM120) treatment resulted in a partial response in a patient with metastatic urothelial carcinoma harboring PIK3CA amplification and TSC1 loss of heterozygosity (PMID: 32767682; NCT01551030). 32767682
PIK3CA E542K TSC1 LOH transitional cell carcinoma no benefit Buparlisib Case Reports/Case Series Actionable In a Phase II trial, Buparlisib (BKM120) treatment resulted in progressive disease in a patient with metastatic urothelial carcinoma harboring PIK3CA E542K and TSC1 loss of heterozygosity (PMID: 32767682; NCT01551030). 32767682
TSC1 Y185* transitional cell carcinoma no benefit Buparlisib Case Reports/Case Series Actionable In a Phase II trial, Buparlisib (BKM120) treatment resulted in progressive disease in a patient with metastatic urothelial carcinoma harboring TSC1 Y185* (PMID: 32767682; NCT01551030). 32767682
TSC1 R424fs transitional cell carcinoma no benefit Buparlisib Case Reports/Case Series Actionable In a Phase II trial, Buparlisib (BKM120) treatment resulted in progressive disease in a patient with metastatic urothelial carcinoma harboring TSC1 R424fs (PMID: 32767682; NCT01551030). 32767682
FGFR3 S249C TSC1 S561fs bladder urothelial carcinoma predicted - sensitive Erdafitinib Case Reports/Case Series Actionable In a clinical case study, Balversa (erdafitinib) treatment resulted in a partial response with a progression-free survival of 19.6 months in a patient with upper tract urothelial carcinoma harboring FGFR3 S249C and TSC1 S561fs (PMID: 37377403). 37377403
FGFR3 S249C FGFR3 E587Q FGFR3 amp PIK3CA E726K TSC1 S561fs bladder urothelial carcinoma predicted - resistant Erdafitinib Case Reports/Case Series Actionable In a clinical case study, FGFR3 E587Q was identified in the post-progression circulating tumor DNA and FGFR3 amplification (>10 copies) and PIK3CA E726K were identified in the post-progression tissue biopsy of a patient with bladder urothelial cancer harboring FGFR3 S249C and TSC1 S561fs who previously responded to Balversa (erdafitinib) treatment (PMID: 37377403). 37377403
FGFR3 S249C TSC1 Q830* bladder urothelial carcinoma predicted - resistant Erdafitinib Case Reports/Case Series Actionable In a clinical case study, TSC1 Q830* was identified in the post-progression tissue biopsy and circulating tumor DNA (ctDNA) together with TSC1 Q830* in the post-progression ctDNA of a patient with bladder urothelial cancer harboring FGFR3 S249C who previously responded to Balversa (erdafitinib) treatment (PMID: 37377403). 37377403