TSC2

Chr 16AD

TSC complex subunit 2

Also known as: LAM, PPP1R160, TSC4

NCBI Gene: 7249 ENSG00000103197 UniProt: P49815 OMIM: 191092

The protein tuberin interacts with hamartin to form the TSC protein complex that negatively regulates mTORC1 signaling, thereby controlling anabolic cell growth. Loss-of-function mutations cause tuberous sclerosis-2, an autosomal dominant disorder characterized by benign tumor growth in multiple organs, as well as lymphangioleiomyomatosis and focal cortical dysplasia type II. The gene is highly intolerant to loss-of-function variants, consistent with its role as a critical tumor suppressor.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.075 OMIM phenotypes

Clinical Summary— TSC2

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

5 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.07LOEUF

pLI 1.000

Z-score 8.37

OE 0.02 (0.01–0.07)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

-0.33Z-score

OE missense 1.03 (0.98–1.08)

1099 obs / 1068.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.02 (0.01–0.07)

0≤0.351.4

Missense OE?1.03 (0.98–1.08)

0≤0.61.4

Synonymous OE?1.48

0≤1.21.6

LoF obs/exp: 2 / 85.4Missense obs/exp: 1099 / 1068.6Syn Z: -8.39

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTSC2-related tuberous sclerosisLOFAD

This gene — mechanism propensity

0.3196th %ile

GOF

0.3689th %ile

LOF

0.74top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.07 · ClinGen HI: Sufficient evidence for dosage pathogenicity

GOF1 literature citation

Literature Evidence

GOFRanek et al. (2019) showed that phosphorylation or gain- or loss-of-function mutations at either of 2 adjacent serine residues in TSC2 (S1365 and S1366 in mice; S1364 and S1365 in humans) could bidirectionally control mTORC1 activity stimulated by growth factors or hemodynamic stress, and consequent1

LOFIntriguingly, the LAM-like features of these cells suggest that haploinsufficiency at the TSC2 locus contributes to LAM pathology, and demonstrated that iPSC reprogramming and SMC lineage differentiation of somatic patient cells with germline mutations was a viable approach to generate LAM-like cell2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

TSC2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Polycythemia VeraEssential ThrombocythaemiaMyelofibrosis

Prevalence Of Germline Gene Mutations In Patients With Myeloproliferative Neoplasms With Family History

NOT YET RECRUITING

NCT06923670Phase NAFondazione Policlinico Universitario Agostino Gemelli IRCCSStarted 2025-05-21

NGS testingNGS analysis for mutations in genes involved in familial predisposition to hematological malignancies

Advanced LymphomaAdvanced Malignant Solid NeoplasmBladder Carcinoma

Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial)

ACTIVE NOT RECRUITING

NCT02465060Phase PHASE2National Cancer Institute (NCI)Started 2015-08-17

AdavosertibAfatinibAfatinib Dimaleate

Advanced Malignant Solid NeoplasmAnn Arbor Stage III Non-Hodgkin LymphomaAnn Arbor Stage IV Non-Hodgkin Lymphoma

Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)

ACTIVE NOT RECRUITING

NCT03155620Phase PHASE2National Cancer Institute (NCI)Started 2017-07-31

Biopsy ProcedureBiospecimen CollectionBone Marrow Aspiration and Biopsy

Malignant Solid Neoplasms

Adapting Treatment to the Tumor Molecular Alterations for Patients With Advanced Solid Tumors: MyOwnSpecificTreatment

RECRUITING

NCT02029001Phase PHASE2Centre Leon BerardStarted 2014-03

Nilotinib (400 mg BID)Everolimus (10 mg QD)Sorafenib (400 mg BID)

Lymphoma, Non-HodgkinMultiple MyelomaAdvanced Solid Tumors

Canadian Profiling and Targeted Agent Utilization Trial (CAPTUR)

RECRUITING

NCT03297606Phase PHASE2Canadian Cancer Trials GroupStarted 2018-03-23