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Gene TSC2
Variant V504D
Impact List missense
Protein Effect loss of function
Gene Variant Descriptions TSC2 V504D does not lie within any known functional domains of the Tsc2 protein (UniProt.org). V504D fails to inhibit Mtorc1 activity as indicated by reduced inhibition of S6k phosphorylation and leads to decreased interaction with Tsc1 in cultured cells (PMID: 31799751).
Associated Drug Resistance
Category Variants Paths

TSC2 mutant TSC2 inact mut TSC2 V504D

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Transcript NM_000548.5
gDNA chr16:g.2064339T>A
cDNA c.1511T>A
Protein p.V504D
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_021055.3 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
XM_011522637.3 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
NM_001114382.3 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
NM_001363528.2 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
NM_001077183.2 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
XM_011522637.2 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
XM_017023615.1 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
XM_011522639.2 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
NM_001370404.1 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
XM_011522639.3 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
NM_001406663.1 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
XM_011522636.3 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
NM_001370405.1 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
XM_011522640.2 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
XM_024450413.1 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
NM_000548.5 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
NM_001406665.1 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
XM_005255531.4 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
NM_001077183.3 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
NM_001406664.1 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
NM_000548.4 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
XM_005255529.4 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
XM_017023616.1 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
NM_001114382.2 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38
XM_011522636.2 chr16:g.2064339T>A c.1511T>A p.V504D RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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 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 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 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 Advanced Solid Tumor no benefit LY3023414 Case Reports/Case Series Actionable In a Phase II trial (NCI-COG Pediatric MATCH), Samotolisib (LY3023414) treatment resulted in no objective responses in pediatric patients with advanced solid tumors harboring PI3K/mTOR pathway mutations, including PTEN (n=6), PIK3CA (n=5), TSC1 (n=2), TSC2 (n=3), and PIK3R1 (n=1), and resulted in a 3-month progression-free survival of 12%, a 6-month overall survival of 44%, and a 12-month overall survival of 15% (PMID: 39298693; NCT03155620). 39298693
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 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 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 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 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 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 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 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 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 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 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