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Gene TSC2
Variant S939A
Impact List missense
Protein Effect unknown
Gene Variant Descriptions TSC2 S939A does not lie within any known functional domains of the Tsc2 protein (UniProt.org). The functional effect of S939A is conflicting, as it results in Tsc2 phosphorylation levels, GAP activity towards Rheb, and binding to 14-3-3 and Hamartin similar to wild-type Tsc2 in vitro, however, also demonstrates altered cellular localization, reduced S6k phosphorylation, increased mitotic cell number (PMID: 23818547, PMID: 16636147, PMID: 12582162, PMID: 30629673), diminished binding to 14-3-3 (PMID: 20412061), and loss of phosphorylation and activation of Mtorc1 upon translation inhibition (PMID: 30684133), and therefore, its effect on Tsc2 protein function is unknown.
Associated Drug Resistance
Category Variants Paths

TSC2 mutant TSC2 S939A

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Transcript NM_000548.5
gDNA chr16:g.2076563_2076564delAGinsGC
cDNA c.2815_2816delAGinsGC
Protein p.S939A
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
XM_017023616 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
NM_001406697.1 chr16:g.2084582_2084583delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
NM_001114382.3 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
NM_001406691.1 chr16:g.2084513T>G c.2815T>G p.S939A RefSeq GRCh38/hg38
NM_001114382 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
XM_011522637.3 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
NM_001363528.2 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
XM_005255529 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
NM_001406665.1 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
NM_001077183 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
NM_000548.4 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
XM_011522640 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
NM_001370405.1 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
NM_001406695.1 chr16:g.2084582_2084583delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
NM_001114382.2 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
NM_001077183.3 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
NM_000548 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
XM_011522637.2 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
XM_011522640.2 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
XM_011522637 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
XM_017023616.1 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
XM_017023615.1 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
XM_011522639 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
NM_001406696.1 chr16:g.2084582_2084583delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
XM_011522639.2 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
XM_005255531.4 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
NM_001406677.1 chr16:g.2079069T>G c.2815T>G p.S939A RefSeq GRCh38/hg38
XM_005255531 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
XM_024450413.1 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
XM_005255529.4 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
XM_017023615 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
NM_001077183.2 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
XM_011522636.3 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
XM_011522636 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
NM_000548.5 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
NM_001406664.1 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
NM_021055.3 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
XM_011522636.2 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
NM_001406663.1 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
NM_001370404.1 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38
XM_011522639.3 chr16:g.2076563_2076564delAGinsGC c.2815_2816delAGinsGC p.S939A RefSeq GRCh38/hg38

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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 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 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 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 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 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 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 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