About TSC2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TSC2 c.4751T>C, p.Leu1584Pro
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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PM1Supporting
PM1 · supporting
The variant p.Leu1584Pro is located within the Rap-GAP domain (residues 1531-1758) of TSC2, a well-characterized critical functional domain responsible for GTPase-activating protein activity essential for mTORC1 inhibition. UniProt annotates multiple nearby residues as functionally characterized: positions 1643 and 1681 abolish GAP activity, and mutagenesis at 1594 decreases GAP activity. Additionally, leucine to proline substitution at position 1584, which resides within an alpha-helical region (residues 1584-1586), is predicted to disrupt local secondary structure.
PM2Supporting
PM2 · supporting
Variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases, consistent with a rare variant. Allele frequency <0.1% threshold for PM2 is met (absent).
PP3Supporting
PP3 · supporting
Multiple in silico tools predict a deleterious effect: REVEL score 0.989 (highly damaging), BayesDel score 0.569902 (deleterious). Additionally, leucine to proline substitution within an alpha-helical segment (residues 1584-1586) of the Rap-GAP domain is mechanistically consistent with structural disruption. SpliceAI predicts no splicing impact (max delta 0.00), indicating the predicted effect is at the protein level.
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: PM1 supporting, PM2 supporting, PP3 supporting; combination = 3 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
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
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.
29 criteria with recorded statuses: 3 met · 17 not met · 3 not assessed · 6 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.4751T>C (p.Leu1584Pro) is a missense variant in exon 37 of TSC2.
The variant is located within the Rap-GAP domain (residues 1531-1758), a critical functional domain of TSC2 responsible for GTPase-activating protein activity essential for mTORC1 inhibition. Leucine 1584 resides within an alpha-helical segment (1584-1586), and substitution to proline is predicted to disrupt helical structure (PM1_supporting).
The variant is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (PM2_supporting).
Multiple in silico tools predict a deleterious effect: REVEL score 0.989 is strongly damaging and BayesDel score 0.569902 supports a deleterious prediction (PP3_supporting).
SpliceAI predicts no splicing impact (max delta score 0.00), indicating the predicted effect is at the protein level rather than through altered splicing.
No variant-specific functional studies were confirmed. PMID:22903760 tested 78 TSC2 variants for functional effects on TORC1 inhibition, but L1584P could not be verified among those tested from available evidence.
ClinVar reports this variant as Uncertain significance (1 star, single submitter from Labcorp/Invitae), which does not contribute to PP5 or BP6.
No de novo, cosegregation, case-control, or detailed phenotype data are available to support PS2, PS4, PP1, or PP4.
With PM1_supporting, PM2_supporting, and PP3_supporting as the only criteria met (3 supporting-level pathogenic criteria), the variant does not reach the threshold for Likely Pathogenic classification under ACMG/AMP 2015 rules. The variant is classified as a Variant of Uncertain Significance (VUS) trending toward pathogenic.
No criteria match.
Met · 3
PM1 SupportingThe variant p.Leu1584Pro is located within the Rap-GAP domain (residues 1531-1758) of TSC2, a well-characterized critical functional domain responsible for GTPase-activating protein activity essential for mTORC1 inhibition. UniProt annotates multiple nearby residues as functionally characterized: positions 1643 and 1681 abolish GAP activity, and mutagenesis at 1594 decreases GAP activity. Additionally, leucine to proline substitution at position 1584, which resides within an alpha-helical region (residues 1584-1586), is predicted to disrupt local secondary structure. Details ▾Hide ▴
Evidence considered
- UniProt P49815: Rap-GAP domain (1531-1758)
- residue 1584 is within an alpha-helix (1584-1586)
- nearby residues functionally characterized (1594 decreased GAP activity
- 1643 and 1681 abolish GAP activity). Leu→Pro is a helix-breaking substitution.
PM2 SupportingVariant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases, consistent with a rare variant. Allele frequency <0.1% threshold for PM2 is met (absent). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- gnomAD v4.1 (exomes/genomes)
- and gnomAD-Canada v1.0.
Sources
PP3 SupportingMultiple in silico tools predict a deleterious effect: REVEL score 0.989 (highly damaging), BayesDel score 0.569902 (deleterious). Additionally, leucine to proline substitution within an alpha-helical segment (residues 1584-1586) of the Rap-GAP domain is mechanistically consistent with structural disruption. SpliceAI predicts no splicing impact (max delta 0.00), indicating the predicted effect is at the protein level. Details ▾Hide ▴
Evidence considered
- REVEL: 0.989 (damaging)
- BayesDel: 0.569902 (deleterious)
- SpliceAI: max delta 0.00 (no splicing effect). Leu→Pro helix-breaking substitution at a helical position in the GAP domain.
Sources
Not met · 17 · evaluated, threshold not reached
PS2 No de novo occurrence data available for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data in ClinVar
- literature
- or evidence sources.
Still missing
- No parental testing data available.
PS4 Variant reported in ClinVar (VCV001052460) as Uncertain significance by a single clinical laboratory (Invitae); no case-control data or statistically significant enrichment in affected individuals available. Details ▾Hide ▴
Evidence considered
- ClinVar: 1 submission
- Uncertain significance
- criteria provided single submitter (1 star).
Still missing
- No case-control or cohort enrichment data.
Sources
PM6 No de novo occurrence data available for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data in any available source.
Still missing
- No parental testing data available.
PP1 No cosegregation data available for this variant. Details ▾Hide ▴
Evidence considered
- No family studies or segregation analysis available.
Still missing
- No family segregation data.
PP4 No detailed phenotype or family history data available. ClinVar lists the associated condition as Tuberous sclerosis 2, but the single submission provides no patient-specific clinical details. Details ▾Hide ▴
Evidence considered
- ClinVar condition: Tuberous sclerosis 2
- no patient-level phenotype data.
Still missing
- No detailed phenotype or family history available.
Sources
PP5 ClinVar classification is Uncertain significance with 1-star review status (criteria provided, single submitter). PP5 requires a reputable source reporting the variant as pathogenic; 1-star VUS does not meet the 3-star expert panel threshold for PP5 application. Details ▾Hide ▴
Evidence considered
- ClinVar VCV001052460: Uncertain significance
- 1 star (Labcorp/Invitae
- single submitter).
Sources
BA1 Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. Does not meet BA1 threshold of allele frequency >1%. Details ▾Hide ▴
Evidence considered
- Allele frequency 0% across all population databases
- BA1 threshold >1% not met.
Sources
BS1 Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. Does not meet BS1 threshold of allele frequency >0.3%. Details ▾Hide ▴
Evidence considered
- Allele frequency 0% across all population databases
- BS1 threshold >0.3% not met.
Sources
BS2 No evidence of observation in healthy adults with expected full penetrance at an early age. Details ▾Hide ▴
Evidence considered
- No data on observation in healthy controls or adult population.
Still missing
- No control population data.
BS3 No functional studies demonstrating no damaging effect on protein function or splicing for this variant. Details ▾Hide ▴
Evidence considered
- REVEL 0.989 and BayesDel 0.569902 predict damaging
- not benign
- effect.
Still missing
- No functional studies demonstrating normal protein function.
BS4 No cosegregation data available; cannot evaluate lack of segregation with disease. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No segregation data.
BP1 TSC2 missense variants are established causes of tuberous sclerosis complex. BP1 applies only to genes where solely truncating variants cause disease, which is not the case for TSC2. Details ▾Hide ▴
Evidence considered
- ClinVar contains pathogenic missense variants in TSC2. TSC2 disease mechanism includes both truncating and missense pathogenic variants.
Sources
BP2 No evidence of observation in trans with a known pathogenic dominant variant in TSC2. Details ▾Hide ▴
Evidence considered
- No data on allelic configuration with other TSC2 variants.
Still missing
- No phasing/allelic data.
BP4 REVEL score 0.989 and BayesDel score 0.569902 predict a damaging effect, contradicting BP4 application. Multiple in silico tools support a deleterious prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.989 (damaging)
- BayesDel: 0.569902 (deleterious). No in silico tools predict benign.
Sources
revelbayesdel
BP5 No evidence of an alternate molecular basis for disease in the affected individual(s). Details ▾Hide ▴
Evidence considered
- No data on other variants found in the same case.
Still missing
- No alternate molecular diagnosis data.
BP6 ClinVar classification is Uncertain significance (1 star, single submitter). No reputable source classifies this variant as benign or likely benign. Details ▾Hide ▴
BP7 NM_000548.4:c.4751T>C is a missense variant (p.Leu1584Pro), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous
- SpliceAI max delta 0.00 confirms no cryptic splice effect but BP7 does not apply to missense.
Sources
Not assessed · 3 · no assessment recorded
PS1 No evidence of a different nucleotide change at c.4751 producing the same amino acid change (p.Leu1584Pro) was identified. Details ▾Hide ▴
Still missing
- No alternative nucleotide changes at c.4751 evaluated.
PS3 No variant-specific functional data confirmed for p.Leu1584Pro. PMID:22903760 (Hoogeveen-Westerveld 2013) tested 78 TSC2 variants for TSC1-TSC2-mediated TORC1 inhibition, but the presence of L1584P among the tested variants could not be verified from available data (full text unavailable, OncoKB reports no variant-specific reviewed functional evidence). Details ▾Hide ▴
Evidence considered
- PMID:22903760 is a functional study of 78 TSC2 variants but L1584P could not be confirmed among them
- OncoKB states no variant-specific reviewed functional evidence.
Still missing
- Full text of PMID:22903760 unavailable
- cannot confirm whether L1584P was among the 78 variants tested. Human review of the paper's supplementary table recommended.
Sources
PP2 HCI prior score not available for TSC2 (gene_not_supported). TSC2 is a known tumor suppressor with disease-causing missense variants, but without gene-specific missense constraint metrics (Z-score, missense depletion data), PP2 cannot be reliably applied. Details ▾Hide ▴
Evidence considered
- HCI prior: gene_not_supported. TSC2 missense variants are established causes of tuberous sclerosis complex.
Still missing
- No TSC2-specific missense constraint data (Z-score or comparable metric).
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000548.4:c.4751T>C (p.Leu1584Pro) is a missense variant, not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). Does not meet PVS1 decision tree eligibility under PMC6185798 generic framework. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Leu1584Pro)
- variant_bucket='other'
- apply_generic_pvs1_framework=false.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/APM3 applies to recessive disorders; TSC2-associated tuberous sclerosis complex is autosomal dominant. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to non-repeat non-truncating variants (in-frame indels, stop-loss); this is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo same-residue comparator variants with a different amino acid change identified as pathogenic. Automated PM5 candidate harvest found 0 candidates at residue 1584. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 same-residue candidates found
- eligible_for_classic_pm5_search=false.
Sources
pm5_candidates
BP3 N/ABP3 applies to in-frame indels; this variant is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
PS5 N/ASkipped per case instructions. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- TSC2
- Transcript
- NM_000548.4
- Coding (HGVS c.)
- NM_000548.4:c.4751T>C
- Protein (HGVS p.)
- NP_000539.2:p.(Leu1584Pro)
- GRCh38
- chr16:2086281 T>C
- GRCh37
- chr16:2136282 T>C
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
- 0.989
- BayesDel
- 0.570
How the predictions were used
PP3 SupportingMultiple in silico tools predict a deleterious effect: REVEL score 0.989 (highly damaging), BayesDel score 0.569902 (deleterious). Additionally, leucine to proline substitution within an alpha-helical segment (residues 1584-1586) of the Rap-GAP domain is mechanistically consistent with structural disruption. SpliceAI predicts no splicing impact (max delta 0.00), indicating the predicted effect is at the protein level. Details ▾Hide ▴
Evidence considered
- REVEL: 0.989 (damaging)
- BayesDel: 0.569902 (deleterious)
- SpliceAI: max delta 0.00 (no splicing effect). Leu→Pro helix-breaking substitution at a helical position in the GAP domain.
Sources
BP4 REVEL score 0.989 and BayesDel score 0.569902 predict a damaging effect, contradicting BP4 application. Multiple in silico tools support a deleterious prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.989 (damaging)
- BayesDel: 0.569902 (deleterious). No in silico tools predict benign.
Sources
revelbayesdel
BP7 NM_000548.4:c.4751T>C is a missense variant (p.Leu1584Pro), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous
- SpliceAI max delta 0.00 confirms no cryptic splice effect but BP7 does not apply to missense.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.989. BayesDel score = 0.569902.
2 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 22903760 ↗Functional assessment of TSC2 variants identified in individuals with tuberous sclerosis complex.Hoogeveen-Westerveld et al. (2013) tested 78 TSC2 missense variants for effects on TSC1-TSC2-mediated TORC1 inhibition. Functional assessment classified 34 variants as pathogenic, 3 as probably pathogenic, and 3 as possibly pathogenic. The specific variant p.Leu1584Pro (c.4751T>C) could not be confirmed among the tested variants from available evidence; OncoKB reports no variant-specific reviewed functional evidence for this alteration.Does not name this variant
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp et al. (2017) describe the Sherloc refinement of ACMG-AMP variant classification criteria. This is a methodological framework paper and does not mention the specific variant NM_000548.4:c.4751T>C (p.Leu1584Pro).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 0.000
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.4751T%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-2136282-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-2086281-T-C?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/16-2086281-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000548.4%3Ac.4751…
- OncoKB ↗www.oncokb.org/gene/TSC2/L1584P
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=TSC2+c.4751T%3EC
- 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
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 1052460)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.989. BayesDel score = 0.569902.
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.