Starting
Initialising…
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TSC2
Final classification
VUS
TSC2 c.3581G>T · p.Trp1194Leu
TSC2

NM_000548.4:c.3581G>T (p.Trp1194Leu) is a missense variant in TSC2, a gene in which loss-of-function is an established mechanism for autosomal dominant tuberous sclerosis complex.

Gene
TSC2
Transcript
NM_000548.4
HGVS · transcript:coding
NM_000548.4:c.3581G>T
Consequence
N/A
GRCh38
chr16:2080348 G>T
GRCh37
chr16:2130349 G>T
Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP3 supporting; combination = 2 supporting, which maps to VUS. ▾
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP3 supporting; combination = 2 supporting, which maps to VUS.
Classification rationale
PM2PP3 VUS
TSC2 c.3581G>T

NM_000548.4:c.3581G>T (p.Trp1194Leu) is a missense variant in TSC2, a gene in which loss-of-function is an established mechanism for autosomal dominant tuberous sclerosis complex.1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.2 In silico predictors support a deleterious effect: REVEL score 0.89 and BayesDel score 0.518, meeting PP3 at supporting strength. SpliceAI predicts no aberrant splicing (max delta 0.02).3 No pathogenic (PVS1, PS1-PS5) or benign (BA1, BS1-BS4) criteria are met beyond PM2_supporting and PP3_supporting.4 Under generic ACMG/AMP 2015 combination rules (PMID:25741868), two supporting pathogenic criteria (PM2 + PP3) without any moderate or strong criteria is insufficient for Likely Pathogenic and results in a final classification of Variant of Uncertain Significance (VUS).5

PM2 + PP3 → VUS
1 pvs1_gene_contextgeneric_acmg_combination_rules
2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
3 revelbayesdelspliceai ↗
4 clinvar ↗pm5_candidates
5 generic_acmg_combination_rules
Gene diagram · NM_000548.4 · variants mapped to exon structure
TSC2 NM_000548.4
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength very strong supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
    Gaps remaining
      Rule
      —
      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
      Error retrieving ClinVar entry.
      ClinVar ↗
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.89. BayesDel score = 0.517806.
      SpliceAI ↗
      Functional / OncoKB screenshot
      Functional Unknown Oncogenic Effect
      OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TSC2, a GTPase-activating protein, is altered by mutation in various cancers, including endometrial and colorectal cancer.
      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 · 8 PMIDs not cited in assessment
      20301399 ↗ Tuberous Sclerosis Complex. CLINVAR
      23519317 ↗ Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. CLINVAR
      23788249 ↗ ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. CLINVAR
      25356965 ↗ ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. CLINVAR
      27854360 ↗ Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. CLINVAR
      34012068 ↗ ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). CLINVAR
      35802134 ↗ ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG). CLINVAR
      28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR