Classification rationale

PVS1PM2 Likely Pathogenic

TSC2 c.3796_3797del

PVS1 (Very Strong): 2-bp deletion causes frameshift p.(Leu1266AlafsTer55), a null variant predicted to trigger nonsense-mediated decay in TSC2, where loss of function is an established disease mechanism. PM2 (Supporting): variant is absent from gnomAD v2.1/v4.1 exomes and gnomAD-Canada genomes (allele frequency 0, below the 0.1% threshold). Overall: Likely Pathogenic, per the ACMG/AMP combination rule PVS1 + 1 supporting criterion (posterior probability 0.988).

PVS1 + PM2 → Likely Pathogenic

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

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PVS1 very strong Pathogenic

Met at very strong: 2-bp deletion causes frameshift p.(Leu1266AlafsTer55), a null variant predicted to trigger nonsense-mediated decay in TSC2, a gene with an established loss-of-function disease mechanism.

pvs1_variant_assessment: variant classified as frameshift (variant_bucket=frameshift) on NM_000548.4, protein NP_000539.2:p.(Leu1266AlafsTer55), suggested_default_strength=PVS1 under PMC6185798; Mutalyzer protein prediction: position_last_original=1808, position_last_predicted=1320 (loss of 488 aa).pvs1_gene_context: TSC2 germline LOF mechanism supported, pvs1_gene_gate='eligible', with caution that no official CSPEC/VCEP exists and generic PVS1 fallback should follow PMC6185798.pvs1_generic_framework: ClinGen SVI PVS1 recommendations (PMC6185798) — null variant + established LOF mechanism + NMD predicted, not in last exon/last 50 bp of penultimate exon -> PVS1 very strong.

pvs1_generic_framework ↗clinvar ↗PMID:10205261 ↗

✓

PM2 supporting Pathogenic

Met at supporting: variant is absent from gnomAD v2.1 and v4.1 exomes and gnomAD-Canada genomes (allele frequency 0, below the 0.1% threshold).

PMID:25741868 — PM2 rule (absent in controls, or at extremely low frequency if recessive, in ESP/1000 Genomes/ExAC) governs; the variant is entirely absent, satisfying the rule without reliance on a numeric AF cutoffgnomad_v2 — variant absent from gnomAD v2.1 exomes (search_status=absent)gnomad_v4 — variant absent from gnomAD v4.1 exomes (search_status=absent)

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗clinvar ↗PMID:25741868 ↗

Assessed · not applied

Pathogenic

PS2 Not assessed: no de novo occurrence data exist for this variant; parental testing results for the proband are missing.

PS3 Not met: no well-established functional study of this exact variant exists; the OncoKB loss-of-function annotation is curated inference, not an experimental assay.

PS4 Not assessed: no case-level data show this exact variant enriched in affected individuals; the two large TSC cohort studies do not report it.

PM6 Not assessed: no parental testing observation, even without parentage confirmation, is reported for this variant.

PP1 Not assessed: no co-segregation data exist; no family carrying this exact variant is reported.

PP3 Not met: SpliceAI max delta 0.01 is far below the 0.2 splice-impact threshold, and missense predictors do not apply to a deletion.

PP4 Not assessed: no proband phenotype or family history is documented to establish a highly specific TSC presentation.

PP5 Not met: no ClinVar expert-panel (3-star) classification exists for this variant; laboratory P/LP labels do not qualify.

Benign

BA1 Not met: allele frequency is 0 in gnomAD v2.1, v4.1, and gnomAD-Canada, far below the >1% BA1 threshold.

BS1 Not met: allele frequency 0 is not greater than the >0.3% threshold expected for this early-onset dominant disorder.

BS2 Not met: no healthy-adult or homozygous observations exist; the variant is absent from all queried population datasets.

BS3 Not met: no functional study shows normal protein function; SpliceAI's low splice score (0.01) does not address the frameshift's protein impact.

BS4 Not assessed: no segregation study exists showing the variant in unaffected carriers or absent in affected relatives.

BP2 Not assessed: no phased observations exist; no proband genotype or cis/trans testing is available for this variant.

BP4 Not met: SpliceAI's low score (0.01) addresses splicing only and cannot offset the frameshift's unambiguous protein-truncating impact.

BP5 Not assessed: no proband workup data exist to show an alternate molecular basis of disease.

BP6 Not met: ClinVar has no benign or likely-benign submissions and no expert-panel classification for this variant.

N/A · 9 PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

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

This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 3724267)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

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

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 ↗

Literature · how each cited paper was used

3papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 6 further PMIDs triaged but not cited — see Sources & References.

Rule & framework references · cited for criterion definitions, not variant evidence

10205261 ↗ Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis.

17304050 ↗ Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States.

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 6 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

20301399 ↗ Tuberous Sclerosis Complex. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR