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Gene Symbol TSC2
Synonyms LAM | PPP1R160 | TSC4
Gene Description TSC2, TSC complex subunit 2, forms a complex with Tsc1 and inhibits mTOR pathway signaling, thus regulating cell growth and metabolism (PMID: 27226234). Germline TSC2 inactivating mutations cause tuberous sclerosis complex and somatic TSC2 mutations have been identified in various cancers, including renal cell carcinoma, sarcoma, and breast cancer (PMID: 27226234, PMID: 30303819, PMID: 28860410, PMID: 28027327).
ACMG Incidental List v3.0:
Yes, Tuberous sclerosis complex (PMID: 34012068)
NCBI Gene ID Chromosome Map Location Canonical Transcript Gene Role
7249 16 16p13.3 NM_000548 Tumor suppressor (PMID: 30606230)

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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 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 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 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 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 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
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 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 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 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 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 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 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 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 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 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 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 Q1178* thyroid cancer predicted - sensitive Everolimus Case Reports/Case Series Actionable In a clinical case study, a thyroid cancer patient harboring TSC2 Q1178* demonstrated an 18-month response to Afinitor (everolimus) (PMID: 25295501; NCT00936858). 25295501
TSC2 loss Advanced Solid Tumor sensitive Buthionine sulfoximine + Sirolimus Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Rapamune (sirolimus) and Buthionine sulfoximine (BSO) resulted in increased production of ROS and cell death in transformed cells deficient for TSC2 in culture, and apoptotic activity and tumor regression in ELT3 cell line xenograft models also deficient for TSC2 (PMID: 27197195). 27197195
PTEN E235* TSC2 G440S endometrial cancer sensitive Miransertib Preclinical - Pdx Actionable In a preclinical study, a patient-derived xenograft (PDX) model of endometrial cancer harboring PTEN E235* and TSC2 G440S was sensitive to Miransertib (ARQ092), demonstrating greater than 90% inhibition of tumor growth (PMID: 26469692). 26469692
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
TSC2 V1067E chromophobe renal cell carcinoma predicted - sensitive Temsirolimus Case Reports/Case Series Actionable In a clinical case study, Torisel (temsirolimus) treatment led to a complete response in metastatic sites and an 80% decrease in primary tumor size in a patient with chromophobe renal cell carcinoma harboring biallelic mutations, TSC2 splice site mutation and TSC2 V1067E (PMID: 29632054). 29632054
TSC2 D1598fs TSC2 D1690fs hepatocellular carcinoma predicted - sensitive Everolimus Case Reports/Case Series Actionable In a clinical study, a hepatocellular carcinoma patient harboring TSC2 D1598fs and TSC2 D1690fs achieved stable disease following treatment with Afinitor (everolimus) (PMID: 30373752). 30373752
TSC2 E96* hepatocellular carcinoma predicted - sensitive Everolimus Case Reports/Case Series Actionable In a clinical study, a hepatocellular carcinoma patient harboring TSC2 E96* achieved stable disease following treatment with Afinitor (everolimus) (PMID: 30373752). 30373752
PIK3CA act mut TSC2 del estrogen-receptor positive breast cancer resistant Alpelisib Preclinical - Cell culture Actionable In a preclinical study, PIK3CA-mutant, ESR1 (ER)-positive breast cancer cell lines with knockout of TSC2 were resistant to treatment with Piqray (alpelisib) in culture (PMID: 33685991). 33685991
PIK3CA act mut TSC2 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 TSC2 were resistant to treatment with Taselisib (GDC-0032) in culture (PMID: 33685991). 33685991
TSC2 R611W giant cell glioblastoma predicted - sensitive Everolimus Case Reports/Case Series Actionable In a clinical case study, Afinitor (everolimus) treatment with adjuvant electromagnetic field therapy resulted in complete remission ongoing 33 months after diagnosis in a patient with gigantocellular glioblastoma harboring TSC2 R611W who was previously treated with surgical resection and radiotherapy (PMID: 31154346). 31154346