About TSC2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TSC2 c.3581G>T, p.(Trp1194Leu)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
Variant is absent from gnomAD v2.1 (0 alleles), gnomAD v4.1 (0 alleles), and gnomAD-Canada v1.0 (0 alleles), meeting the <0.1% allele frequency threshold for PM2 under the generic ACMG/AMP framework.
PP3Supporting
PP3 · supporting
Multiple in silico tools predict a deleterious effect: REVEL score 0.89 (high-confidence damaging range, threshold >0.5), BayesDel score 0.518 (above deleterious threshold). SpliceAI predicts no splicing impact (max delta 0.02), which is expected for a missense variant and does not negate the protein-level predictions.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 19 not met · 1 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.
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).
No pathogenic (PVS1, PS1-PS5) or benign (BA1, BS1-BS4) criteria are met beyond PM2_supporting and PP3_supporting.
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).
No criteria match.
Met · 2
PM2 SupportingVariant is absent from gnomAD v2.1 (0 alleles), gnomAD v4.1 (0 alleles), and gnomAD-Canada v1.0 (0 alleles), meeting the <0.1% allele frequency threshold for PM2 under the generic ACMG/AMP framework. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0/0 alleles)
- absent from gnomAD v4.1 (0/0 alleles)
- absent from gnomAD-Canada v1.0 (0/0 alleles).
Sources
PP3 SupportingMultiple in silico tools predict a deleterious effect: REVEL score 0.89 (high-confidence damaging range, threshold >0.5), BayesDel score 0.518 (above deleterious threshold). SpliceAI predicts no splicing impact (max delta 0.02), which is expected for a missense variant and does not negate the protein-level predictions. Details ▾Hide ▴
Evidence considered
- REVEL 0.89 (deleterious)
- BayesDel 0.517806 (deleterious)
- SpliceAI max delta 0.02 (no splicing impact — consistent with missense mechanism).
Sources
Not met · 19 · evaluated, threshold not reached
PS2 No de novo occurrence with confirmed paternity and maternity has been reported for this variant in population databases or the literature. Details ▾Hide ▴
Evidence considered
- LOVD TSC2 database search returned no entry
- PubMed search for 'TSC2 W1194L de novo' yielded no relevant results.
Still missing
- No de novo case identified in any public variant database or literature source.
Sources
PS3 No variant-specific functional studies identified. REVEL score of 0.89 and BayesDel score of 0.518 are in silico predictions, not well-established functional assays per ACMG/AMP guidelines. OncoKB reports unknown oncogenic effect with no curated functional evidence for this variant. Details ▾Hide ▴
Evidence considered
- REVEL 0.89 (deleterious range)
- BayesDel 0.517806
- no variant-specific functional assay data in curated databases or PubMed.
Still missing
- Absence of any in vitro or in vivo functional characterization of p.Trp1194Leu.
Sources
PS4 Variant is absent from gnomAD v2.1 and v4.1; no case-control data available to demonstrate statistically significant enrichment in affected individuals versus controls. ClinVar contains a single VUS submission with no proband counts. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1
- single ClinVar VUS submission
- no case-control or cohort data.
Still missing
- No proband counts
- case-control study
- or cohort frequency data available.
Sources
PM1 Residue 1194 lies between the N-terminal hamartin-binding domain and the C-terminal GAP domain of tuberin. No statistically significant mutational hotspot has been identified at this position, and the variant is not located in a critical or well-established functional domain without benign variation. Details ▾Hide ▴
Evidence considered
- No hotspot significance at residue 1194
- residue lies between annotated functional domains.
PM6 No report of this variant occurring as an assumed de novo event (without confirmation of paternity and maternity). Not identified in LOVD, ClinVar, or the literature as a de novo observation. Details ▾Hide ▴
Evidence considered
- LOVD TSC2 database: no entry
- PubMed search for 'TSC2 3581G>T de novo' returned no relevant result.
Still missing
- No de novo report
- assumed or confirmed
- available.
Sources
PP1 No cosegregation data available. No families with this variant and multiple affected members have been reported in databases or the literature. Details ▾Hide ▴
Evidence considered
- No family studies or cosegregation data identified in LOVD or PubMed.
Still missing
- Complete lack of family segregation information.
PP4 No patient phenotype or family history data available for this variant. Cannot assess whether the proband's clinical presentation is highly specific for TSC2-related tuberous sclerosis complex. Details ▾Hide ▴
Evidence considered
- No proband phenotype or clinical data available in the evidence sources.
Still missing
- Patient phenotype and family history not provided.
PP5 No reputable source reports this variant as pathogenic. ClinVar classification is VUS (criteria provided, single submitter). All eight ClinVar-associated PMIDs are general guideline or review articles (GeneReviews chapter, ACMG secondary findings policies, Sherloc criteria) that do not address this specific variant. Details ▾Hide ▴
Evidence considered
- ClinVar: VUS
- single submitter. All 8 ClinVar-attached PMIDs are non-variant-specific guidelines/reviews.
Sources
BA1 Variant is absent from gnomAD v2.1 and v4.1; allele frequency is far below the >1% threshold for BA1. Details ▾Hide ▴
BS1 Variant is absent from gnomAD v2.1 and v4.1; allele frequency is far below the >0.3% threshold for BS1 under generic ACMG. Details ▾Hide ▴
BS2 No observation of this variant in a healthy adult individual where full penetrance would be expected at an early age. TSC2-related disease typically manifests in childhood; observation in an unaffected adult could support BS2, but no such observation exists. Details ▾Hide ▴
Evidence considered
- No observation in healthy adult controls.
Still missing
- No data on variant carriers without clinical phenotype.
BS3 No well-established in vitro or in vivo functional studies demonstrate a neutral or normal effect of p.Trp1194Leu on protein function. No functional data exist for this variant. Details ▾Hide ▴
Evidence considered
- PubMed search for 'TSC2 W1194L assay benign' returned no results
- no functional studies found.
Still missing
- No functional characterization of this variant.
BS4 No segregation data available to demonstrate lack of cosegregation with disease in affected family members. No families with this variant have been reported. Details ▾Hide ▴
Evidence considered
- No family segregation information or non-segregation observations available.
Still missing
- No family studies to evaluate segregation.
BP1 Tuberous sclerosis complex is caused by both truncating and missense pathogenic variants in TSC2. Missense variants are an established disease mechanism in this gene, so BP1 (missense variant in a gene where only truncating variants cause disease) does not apply. Details ▾Hide ▴
Evidence considered
- TSC2 LOF mechanism supported
- but missense pathogenic variants are well-documented in TSC2-related tuberous sclerosis complex.
Sources
pvs1_gene_context
BP2 No observation of this variant in trans with a known pathogenic TSC2 variant in an unaffected individual. TSC2-related disease is autosomal dominant with full penetrance expected at an early age, so an observation in trans in a healthy individual would support BP2, but no such observation exists. Details ▾Hide ▴
Evidence considered
- Not observed in trans with any pathogenic TSC2 variant.
Still missing
- No multi-variant reports available.
BP4 Multiple in silico tools predict a deleterious effect, not a benign one: REVEL 0.89 (damaging), BayesDel 0.518 (deleterious). BP4 requires multiple lines of computational evidence suggesting no impact on protein function, which is contradicted by the available scores. Details ▾Hide ▴
Evidence considered
- REVEL 0.89 (deleterious)
- BayesDel 0.517806 (deleterious). Both contradict a benign prediction.
Sources
BP5 No observation of this variant in a case where an alternate molecular basis for disease was identified. BP5 requires a variant found in a patient with a clear alternative genetic etiology. Details ▾Hide ▴
Evidence considered
- No data indicating co-occurrence with an alternate molecular diagnosis.
Still missing
- No multi-variant or alternate diagnosis reports.
BP6 No reputable source reports this variant as benign. ClinVar classification is VUS from a single submitter. BP6 requires a reputable source to have classified the variant as benign. Details ▾Hide ▴
PS5 No reputable source reports this variant as pathogenic. ClinVar classification is Uncertain Significance from a single submitter (criteria provided, single submitter review status). The eight ClinVar-associated PMIDs are general guideline or review articles that do not address this specific variant. Details ▾Hide ▴
Evidence considered
- ClinVar: VUS
- single submitter
- review status criteria provided single submitter. No expert panel or reputable source pathogenic assertion.
Sources
Not assessed · 1 · no assessment recorded
PP2 HCI prior score not available for TSC2. Cannot determine whether the gene has a low rate of benign missense variation to satisfy PP2 criteria. This criterion requires evidence that missense variants are a common mechanism of disease and that benign missense variation is rare in the gene. Details ▾Hide ▴
Evidence considered
- HCI prior not found for this coding variant
- no gene-level missense constraint metric available in the evidence brief.
Still missing
- No HCI prior or other gene-level missense constraint score available for TSC2.
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (p.Trp1194Leu); does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Apply_generic_pvs1_framework is false per pvs1_variant_assessment. Details ▾Hide ▴
Evidence considered
- Missense substitution at c.3581G>T produces p.Trp1194Leu
- not a predicted null variant.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/ATryptophan at position 1194 is encoded only by TGG. No alternate nucleotide change at this codon can produce the same W1194L missense change, so no comparator variant with the same amino acid change exists. Details ▾Hide ▴
Evidence considered
- Trp (TGG) has a single codon
- only c.3581G>T yields W1194L.
PM5 N/ANo pathogenic missense variant identified at the same amino acid residue (Trp1194) to serve as a comparator. pm5_candidates.json confirms zero same-residue candidates; eligible_for_classic_pm5_search is false. Details ▾Hide ▴
Evidence considered
- Zero same-residue candidates collected
- no comparator pathogenic variant at W1194.
Sources
pm5_candidates
BP7 N/AThis is a missense variant (c.3581G>T, p.Trp1194Leu), not a synonymous variant with no predicted splice impact. BP7 applies only to silent variants. Details ▾Hide ▴
Evidence considered
- Missense substitution producing p.Trp1194Leu
- BP7 is restricted to synonymous variants.
Identifiers
- Gene
- TSC2
- Transcript
- NM_000548.4
- Coding (HGVS c.)
- NM_000548.4:c.3581G>T
- Protein (HGVS p.)
- NP_000539.2:p.(Trp1194Leu)
- GRCh38
- chr16:2080348 G>T
- GRCh37
- chr16:2130349 G>T
- ClinVar
- 2865251
Gene diagram
Every interpreted variant in TSC2, mapped onto the exon structure of NM_000548.4. Select a row to find it on the plot.
TSC2NM_000548.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in TSC2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.890
- BayesDel
- 0.518
How the predictions were used
PP3 SupportingMultiple in silico tools predict a deleterious effect: REVEL score 0.89 (high-confidence damaging range, threshold >0.5), BayesDel score 0.518 (above deleterious threshold). SpliceAI predicts no splicing impact (max delta 0.02), which is expected for a missense variant and does not negate the protein-level predictions. Details ▾Hide ▴
Evidence considered
- REVEL 0.89 (deleterious)
- BayesDel 0.517806 (deleterious)
- SpliceAI max delta 0.02 (no splicing impact — consistent with missense mechanism).
Sources
BP4 Multiple in silico tools predict a deleterious effect, not a benign one: REVEL 0.89 (damaging), BayesDel 0.518 (deleterious). BP4 requires multiple lines of computational evidence suggesting no impact on protein function, which is contradicted by the available scores. Details ▾Hide ▴
Evidence considered
- REVEL 0.89 (deleterious)
- BayesDel 0.517806 (deleterious). Both contradict a benign prediction.
Sources
BP7 N/AThis is a missense variant (c.3581G>T, p.Trp1194Leu), not a synonymous variant with no predicted splice impact. BP7 applies only to silent variants. Details ▾Hide ▴
Evidence considered
- Missense substitution producing p.Trp1194Leu
- BP7 is restricted to synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.89. BayesDel score = 0.517806.
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 20301399 ↗Tuberous Sclerosis Complex.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 23519317 ↗Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions.Schaefer GB et al. · 2013No paper-specific finding is recorded.
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PMID 23788249 ↗ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.Green RC et al. · 2013No paper-specific finding is recorded.
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PMID 25356965 ↗ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.ACMG Board of Directors · 2015No paper-specific finding is recorded.
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PMID 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.Kalia SS et al. · 2017No paper-specific finding is recorded.
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PMID 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).Miller DT et al. · 2021No paper-specific finding is recorded.
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PMID 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).Miller DT et al. · 2022No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
1 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_000548.4%3Ac.3581G%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-2130349-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-2080348-G-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/16-2080348-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000548.4%3Ac.3581…
- OncoKB ↗www.oncokb.org/gene/TSC2/W1194L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=TSC2+c.3581G%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
Error retrieving ClinVar entry.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.89. BayesDel score = 0.517806.
Functional
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.