TSC2
Chr 16ADTSC complex subunit 2
Also known as: LAM, PPP1R160, TSC4
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.
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Among the most LoF-intolerant genes (~top 3%)
Tolerant to missense variation
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.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
300 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 20 | 0 | 1 | 1 | 22 |
Likely Pathogenic | 0 | 3 | 0 | 0 | 3 |
VUS | 1 | 122 | 20 | 0 | 143 |
Likely Benign | 0 | 3 | 74 | 41 | 118 |
Benign | 0 | 1 | 3 | 1 | 5 |
Conflicting | — | 9 | |||
| Total | 21 | 129 | 98 | 43 | 300 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in 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.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Canadian Profiling and Targeted Agent Utilization Trial (CAPTUR)
RECRUITINGPrevalence Of Germline Gene Mutations In Patients With Myeloproliferative Neoplasms With Family History
NOT YET RECRUITINGAdapting Treatment to the Tumor Molecular Alterations for Patients With Advanced Solid Tumors: MyOwnSpecificTreatment
RECRUITINGTargeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial)
ACTIVE NOT RECRUITINGTargeted 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 RECRUITINGPhase 2 Basket Trial of Nab-sirolimus in Patients With Malignant Solid Tumors With Pathogenic Alterations in TSC1/TSC2 Genes (PRECISION 1)
ACTIVE NOT RECRUITINGExternal Resources
Links to major genomics databases and tools