Analysis in progress
Initialising…
0%
complete
This report is still being assembled — sections appear as each stage finishes. It isn't final yet.
TSC2
Final classification
VUS
PVS1PM2
TSC2
c.5335del
p.Gln1779ArgfsTer47
frameshift · exon 42
Gene context NCBI Gene ↗ OncoKB ↗

TSC2 is a tumor suppressor gene that encodes tuberin, a growth-inhibitory protein. Tuberin teams up with hamartin to form the TSC protein complex, which keeps cell growth in check by dampening mTORC1 signaling. Mutations in TSC2 cause tuberous sclerosis, a disorder featuring benign and occasionally malignant tumors, and are also linked to lymphangioleiomyomatosis. Loss-of-function changes in TSC2 are seen in some cancers, such as liver and endometrial cancers, and can make tumors sensitive to mTOR-inhibiting drugs.

This variant

TSC2 loss-of-function drives tuberous sclerosis and related tumors by releasing mTORC1 growth signaling, but this frameshift sits at the extreme C-terminus of tuberin: it escapes nonsense-mediated decay and replaces only the final 29 residues (~1.6% of the protein), leaving most of the growth-inhibitory protein intact. With no functional or clinical evidence yet showing whether this altered tail disrupts tuberin's tumor-suppressor activity, the variant remains a VUS.

Transcript
NM_000548.4
HGVS · transcript:coding
NM_000548.4:c.5335del
GRCh38
chr16:2088520 AC>A
GRCh37
chr16:2138521 AC>A
Basis No TSC2-specific VCEP framework was available, so generic ACMG/AMP 2015 rules applied: PVS1 (supporting) plus PM2 (supporting), two supporting criteria, map to VUS. ▾
No TSC2-specific VCEP framework was available, so generic ACMG/AMP 2015 rules applied: PVS1 (supporting) plus PM2 (supporting), two supporting criteria, map to VUS.
Classification rationale
PVS1PM2 VUS
TSC2 c.5335del frameshift · exon 42

PVS1 (Supporting): terminal-exon frameshift escapes nonsense-mediated decay and alters only 29 of 1807 residues (~1.6% of tuberin), below the ~10% critical-region threshold. PM2 (Supporting): variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with extreme rarity. Combination: two supporting criteria under generic ACMG/AMP 2015 rules yield a VUS (variant of uncertain significance).

PVS1 + PM2 → VUS
Gene diagram · NM_000548.4 · variants mapped to exon structure
TSC2 NM_000548.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 17 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength Supporting Moderate Strong Very strong
✓
PVS1 supporting review Pathogenic
Met (supporting): frameshift escapes nonsense-mediated decay in the terminal exon, altering only 29 of 1807 residues (~1.6%), far below the ~10% critical-region threshold.
case_summary.json pvs1_variant_assessment: variant classified consequence_class='frameshift', variant_bucket='frameshift', framework_source PMC6185798, apply_generic_pvs1_framework=true, suggested_default_strength='PVS1' pending downgrade checks for NMD escape and exon/region importance.case_summary.json pvs1_variant_assessment.downgrade_considerations explicitly flag: confirm transcript relevance, downgrade if predicted truncation escapes NMD or affects only a non-critical distal region, downgrade/withhold if the affected exon is not biologically relevant or is enriched for population LoF variation.prefetch.json mutalyzer selector_short exon coordinates show the transcript has 42 total exons and variant_exonic_positions (start_exon=end_exon=42 for both GRCh37/GRCh38) place c.5335del in the final exon (exon 42/42), spanning c.5260-*110.
pvs1_generic_framework ↗
✓
PM2 supporting Pathogenic
Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with extreme rarity in TSC2-related disease.
gnomAD v2.1 reports NM_000548.4:c.5335del as absent.gnomAD v4.1 reports NM_000548.4:c.5335del as absent.gnomAD-Canada v1.0 reports NM_000548.4:c.5335del as absent.
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
Assessed · not applied · 4 not met · 13 not assessed
Pathogenic
PS2 Not assessed: no parental genotypes, trio testing, or de novo documentation was available.
PS3 Not assessed: no functional assay results for this specific variant, with controls, were available.
PS4 Not assessed: no affected-case series, case-control comparison, or enrichment data for this variant was available.
PM6 Not assessed: no unconfirmed de novo observation in an affected proband was reported.
PP1 Not assessed: no affected relatives, informative meioses, or segregation analysis were documented.
PP3 Not met: SpliceAI max delta 0.00 shows no predicted splice impact for this frameshift variant.
PP4 Not assessed: no proband phenotype or clinical diagnosis was available for evaluation.
PP5 Not assessed: the variant has no ClinVar entry or expert-panel assertion.
Benign
BA1 Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada, below the stand-alone benign frequency threshold.
BS1 Not met: the variant is absent from population databases rather than present above the benign disease-frequency threshold.
BS2 Not assessed: no data on occurrence in healthy adults or homozygotes from population cohorts was available.
BS3 Not assessed: no variant-specific functional assay showing no damaging effect was available.
BS4 Not assessed: no unaffected carriers, non-segregation data, or phenotype-confirmed family dataset was provided.
BP2 Not assessed: no second pathogenic variant or phase information was documented for this variant.
BP4 Not met: SpliceAI max delta 0.00 suggests no splice disruption, but a benign splice score does not offset the frameshift's loss-of-function consequence.
BP5 Not assessed: no evidence of an alternative genetic cause of the phenotype was available.
BP6 Not assessed: the variant is absent from ClinVar with no benign or likely-benign classification.
N/A · 9 PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
SpliceAI ↗
Functional / OncoKB screenshot
Functional Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 4 PMIDs not cited in assessment
14561707 ↗ Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. ONCOKB
14729330 ↗ TSC2: filling the GAP in the mTOR signaling pathway. ONCOKB
24529379 ↗ Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. ONCOKB
25724664 ↗ Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus. ONCOKB