About TSC1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TSC1 c.1801C>A, p.(Pro601Thr)
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (genomes), meeting the PM2 criterion for a rare variant with population frequency below 0.1%.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of in silico evidence predict no damaging effect: BayesDel score -0.201 (benign prediction), SpliceAI max delta 0.02 (no predicted splice impact), and REVEL score 0.453 (indeterminate, below standard pathogenic thresholds). The convergence of benign and neutral computational predictions meets BP4 at supporting level.
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, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, 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
2 reported laboratory submissions
2 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. TSC1, a scaffold protein, is frequently altered by mutation in bladder 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_000368.4:c.1801C>A (p.Pro601Thr) is a missense variant in exon 15 of TSC1, which encodes a scaffold protein in the mTOR pathway; loss-of-function variants in TSC1 cause tuberous sclerosis complex (autosomal dominant).
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2).
Multiple in silico tools predict no damaging effect: BayesDel score -0.201 (benign), SpliceAI max delta 0.02 (no splice impact), and REVEL score 0.453 (indeterminate, below pathogenic thresholds), meeting BP4 at supporting level.
ClinVar classifies this variant as Uncertain Significance (criteria provided, single submitter, 2 clinical laboratories); no expert panel classification is available.
No variant-specific functional studies, segregation data, case-control evidence, de novo observations, or same-residue pathogenic comparators were identified.
Overall, PM2 (supporting) and BP4 (supporting benign) are the only applicable criteria. These two opposing supporting-level criteria offset each other, resulting in a classification of Uncertain Significance per ACMG/AMP 2015 combination rules.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (genomes), meeting the PM2 criterion for a rare variant with population frequency below 0.1%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (0 alleles).
- gnomAD v4.1: absent (0 alleles).
- gnomAD-Canada v1.0: absent (0 alleles).
Sources
BP4 SupportingMultiple lines of in silico evidence predict no damaging effect: BayesDel score -0.201 (benign prediction), SpliceAI max delta 0.02 (no predicted splice impact), and REVEL score 0.453 (indeterminate, below standard pathogenic thresholds). The convergence of benign and neutral computational predictions meets BP4 at supporting level. Details ▾Hide ▴
Evidence considered
- BayesDel: -0.201 (benign prediction).
- SpliceAI max delta: 0.02 (no splice impact).
- REVEL: 0.453 (indeterminate
- below pathogenic threshold).
Sources
Not met · 19 · evaluated, threshold not reached
PS2 No de novo observation has been reported for this variant in the available evidence; no parentage-confirmed de novo data identified in ClinVar, literature, or databases. Details ▾Hide ▴
Evidence considered
- ClinVar submissions do not report de novo origin.
- No literature reports of de novo occurrence.
Still missing
- No trio or de novo testing data available.
PS3 No variant-specific functional studies have been reported. OncoKB classifies this variant as Unknown Oncogenic Effect with no variant-level functional evidence curated. No functional data identified in literature or databases. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific reviewed functional evidence.
- No functional studies identified in PubMed literature for this variant.
Still missing
- No functional assay data available for p.Pro601Thr.
Sources
PS4 Variant is absent from gnomAD but no case-control or statistical enrichment evidence in affected individuals has been reported. No published cohort data demonstrating significant enrichment in cases versus controls for this variant. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD v2.1
- v4.1
- and Canada.
- No case-control or cohort enrichment data available.
Still missing
- No case-control study data
- variant prevalence in affected individuals unknown beyond ClinVar VUS submissions.
PM1 Variant does not lie in a statistically significant mutational hotspot; hotspot analysis negative. Pro601 is not within an established functional domain where pathogenic missense variants cluster preferentially. Details ▾Hide ▴
Evidence considered
- Hotspot analysis: not in a statistically significant hotspot.
- No known pathogenic missense cluster at position 601.
PM6 No de novo observation has been reported for this variant. No confirmed de novo occurrence with maternity/paternity confirmation available in ClinVar or literature. Details ▾Hide ▴
Evidence considered
- Same evidence basis as PS2
- no de novo data identified.
Still missing
- No trio or de novo testing data available.
PP1 No segregation data have been reported for this variant. No family studies demonstrating cosegregation with disease are available. Details ▾Hide ▴
Evidence considered
- No segregation analysis data in ClinVar or literature.
Still missing
- No family segregation studies available.
PP2 PP2 is applied when a gene has a low rate of benign missense variation and missense variants are a common disease mechanism. TSC1 has diverse pathogenic variant types (truncating, missense, splice); there is insufficient evidence to establish that TSC1 meets the PP2 gene-level threshold for this specific variant. Details ▾Hide ▴
Evidence considered
- TSC1 disease mechanism includes both truncating and missense pathogenic variants.
- No gene-specific PP2 calibration data available without a CSPEC/VCEP framework.
Still missing
- No CSPEC/VCEP framework available to provide gene-level PP2 calibration.
PP3 In silico predictions do not support a deleterious effect: REVEL score 0.453 (below 0.5 threshold for pathogenic prediction), BayesDel score -0.201 (benign prediction), SpliceAI max delta 0.02 (no predicted splice impact). Multiple lines of computational evidence do not converge on a damaging prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.453 (indeterminate
- below pathogenic threshold).
- BayesDel: -0.201 (benign prediction).
- SpliceAI max delta: 0.02 (no splice impact).
Sources
PP4 No patient phenotype data are available for this specific variant. No clinical case descriptions with detailed phenotype have been published. Details ▾Hide ▴
Evidence considered
- No published case reports with phenotype data for this variant.
Still missing
- No phenotype data available for patients harboring this variant.
PP5 ClinVar classification is Uncertain Significance (criteria provided, single submitter, 2 clinical laboratories). This does not constitute a reputable source reporting the variant as pathogenic. No expert panel or professional society has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar: 2 submitters
- both VUS
- review status: criteria provided
- single submitter.
- No expert panel classification available.
Sources
BA1 Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, far below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF: 0%.
- gnomAD v4.1 AF: 0%.
- gnomAD-Canada AF: 0%.
Sources
BS1 Variant is absent from gnomAD. Allele frequency is 0%, below the 0.3% BS1 threshold. Absence from population databases does not satisfy BS1. Details ▾Hide ▴
Evidence considered
- Variant is absent from gnomAD
- AF = 0%.
Sources
BS2 Variant is absent from gnomAD; no evidence of observation in healthy adults. BS2 requires observation of the variant in a healthy adult individual for a fully penetrant dominant disorder; absence from population databases precludes its application. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD
- no healthy adult carriers identified.
BS3 No functional studies have been reported demonstrating a neutral or benign effect for this variant. OncoKB classification is Unknown Oncogenic Effect and does not constitute evidence of no deleterious impact. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect.
- No benign functional data identified.
Still missing
- No functional assay data available for p.Pro601Thr.
Sources
BS4 No segregation data demonstrating non-segregation with disease are available. No family studies have been reported for this variant. Details ▾Hide ▴
Evidence considered
- No family segregation studies available.
Still missing
- No segregation data for this variant.
BP1 BP1 applies to missense variants in genes where only truncating variants cause disease. TSC1 has both missense and truncating pathogenic variants associated with tuberous sclerosis complex; therefore BP1 is not applicable to TSC1 missense variants. Details ▾Hide ▴
Evidence considered
- TSC1 is associated with both missense and truncating pathogenic variants
- BP1 not applicable.
BP2 No evidence of observation in trans with a known pathogenic variant for this fully penetrant autosomal dominant disorder. Details ▾Hide ▴
Evidence considered
- No trans configuration data available.
Still missing
- No trans observation data.
BP5 No evidence that an alternative molecular basis explains disease in any case where this variant was observed. No case-level data available to evaluate BP5. Details ▾Hide ▴
Evidence considered
- No case data available with alternative molecular diagnoses.
Still missing
- No case-level clinical data.
BP6 ClinVar classification is Uncertain Significance, not Benign or Likely Benign. BP6 requires a reputable source to classify the variant as benign/likely benign, which has not occurred. Details ▾Hide ▴
Not assessed · 1 · no assessment recorded
PS1 No known pathogenic missense variant at the same amino acid residue (Pro601) with a different amino acid change was identified. Pm5_candidates analysis found no same-residue pathogenic comparators, precluding application of PS1. Details ▾Hide ▴
Evidence considered
- pm5_candidates analysis found zero same-residue candidates at Pro601.
Still missing
- No known pathogenic comparator at Pro601
- PS1 cannot be applied without an established pathogenic variant at the same residue.
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (p.Pro601Thr) in exon 15; does not fulfill default null-variant criteria (nonsense, frameshift, or canonical ±1,2 splice sites). Per ClinGen SVI PVS1 framework (PMC6185798), generic PVS1 does not apply to missense variants. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not a null variant
- pvs1_variant_assessment confirms variant_bucket='other' and apply_generic_pvs1_framework=false.
Sources
PM5 N/ANo same-residue pathogenic missense comparator identified. PM5 candidates analysis found no eligible pathogenic or likely pathogenic variants at Pro601 with a different amino acid change. Details ▾Hide ▴
Evidence considered
- pm5_candidates analysis: found=false
- zero same-residue candidates at Pro601.
BP7 N/AMissense variant (c.1801C>A, p.Pro601Thr). BP7 applies only to synonymous or non-coding variants with no predicted splice impact; this is a non-synonymous amino acid substitution. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 only for synonymous/intronic variants.
PS5 N/ATSC1-associated tuberous sclerosis complex is an autosomal dominant disorder. PS5 applies to recessive disorders where a pathogenic variant is found in trans. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- TSC1
- Transcript
- NM_000368.4
- Coding (HGVS c.)
- NM_000368.4:c.1801C>A
- Protein (HGVS p.)
- NP_000359.1:p.(Pro601Thr)
- GRCh38
- chr9:132905777 G>T
- GRCh37
- chr9:135781164 G>T
- ClinVar
- 820107
Gene diagram
Every interpreted variant in TSC1, mapped onto the exon structure of NM_000368.4. Select a row to find it on the plot.
TSC1NM_000368.4
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in TSC1
—
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
- 0.453
- BayesDel
- -0.201
How the predictions were used
BP4 SupportingMultiple lines of in silico evidence predict no damaging effect: BayesDel score -0.201 (benign prediction), SpliceAI max delta 0.02 (no predicted splice impact), and REVEL score 0.453 (indeterminate, below standard pathogenic thresholds). The convergence of benign and neutral computational predictions meets BP4 at supporting level. Details ▾Hide ▴
Evidence considered
- BayesDel: -0.201 (benign prediction).
- SpliceAI max delta: 0.02 (no splice impact).
- REVEL: 0.453 (indeterminate
- below pathogenic threshold).
Sources
PP3 In silico predictions do not support a deleterious effect: REVEL score 0.453 (below 0.5 threshold for pathogenic prediction), BayesDel score -0.201 (benign prediction), SpliceAI max delta 0.02 (no predicted splice impact). Multiple lines of computational evidence do not converge on a damaging prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.453 (indeterminate
- below pathogenic threshold).
- BayesDel: -0.201 (benign prediction).
- SpliceAI max delta: 0.02 (no splice impact).
Sources
BP7 N/AMissense variant (c.1801C>A, p.Pro601Thr). BP7 applies only to synonymous or non-coding variants with no predicted splice impact; this is a non-synonymous amino acid substitution. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 only for synonymous/intronic variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.453. BayesDel score = -0.200853.
6 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
-
PMID 23519317 ↗Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions.Schaefer GB et al. · 20132013 ACMG guideline on clinical genetics evaluation for autism spectrum disorders. Does not discuss TSC1 variants or the specific variant NM_000368.4:c.1801C>A.Does not name this variant
-
PMID 25356965 ↗ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.ACMG Board of Directors · 2015ACMG policy statement on updated recommendations for secondary findings reporting in clinical genome-scale sequencing. Lists TSC1 as a gene recommended for secondary findings analysis but does not mention any specific variant or the variant NM_000368.4:c.1801C>A.Does not name this variant
Quoted passage
Tuberous sclerosis complex: TSC1, TSC2 (AD, KP and EP)
Gene list table referencing TSC1/TSC2 for Tuberous Sclerosis Complex
-
PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. Does not mention TSC1 or any specific variant; focused on cancer predisposition syndrome referral criteria.Does not name this variant
-
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. · 2017ACMG SF v2.0 list of genes recommended for secondary findings reporting from clinical exome and genome sequencing. TSC1 is listed as associated with Tuberous Sclerosis Complex, but no specific variant is discussed or mentioned.Does not name this variant
Quoted passage
Tuberous sclerosis complex: TSC1, TSC2
Table 1, ACMG SF v2.0 gene list
-
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. · 2022ACMG SF v3.1 updated list of genes recommended for secondary findings reporting. TSC1 and TSC2 are listed under Tuberous Sclerosis Complex with autosomal dominant inheritance; no specific variant information is included.Does not name this variant
Quoted passage
Tuberous sclerosis complex: TSC1, TSC2 (AD, All P and LP)
Table 1, ACMG SF v3.1 gene list
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Sherloc comprehensive refinement of ACMG-AMP variant classification criteria. A methodology paper that does not discuss TSC1 or any specific variant. Cited in ClinVar by Invitae submission as a supporting reference for classification methodology.Does not name this variant
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
2 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_000368.4%3Ac.1801C%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-135781164-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-132905777-G-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-132905777-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000368.4%3Ac.1801…
- OncoKB ↗www.oncokb.org/gene/TSC1/P601T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=TSC1+c.1801C%3EA
- 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 = 0.453. BayesDel score = -0.200853.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TSC1, a scaffold protein, is frequently altered by mutation in bladder 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.