0%
TSC1c.1022C>TLikely benign
Print report
Variant interpretation report

TSC1 c.1022C>T, p.(Pro341Leu)

NM_000368.4:c.1022C>T NP_000359.1:p.(Pro341Leu) View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About TSC1

No gene-level summary was recorded for this case.

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: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 and present in gnomAD v4.1 at extremely low frequency (AF=0.000062%, 10/1,610,852 alleles, 0 homozygotes), well below the PM2 threshold of less than 0.1%.

Benign criteria applied · 2
BS2Supporting
BS2 · supporting

This variant is observed in 10 heterozygous individuals in gnomAD v4.1 (0 homozygotes). TSC is a dominant disorder with near-complete penetrance and early childhood onset. Observation in a population database of presumably healthy adults is inconsistent with a fully penetrant pathogenic variant, supporting a benign interpretation.

BP4Supporting
BP4 · supporting

BayesDel score 0.161 is in the benign range (threshold greater than 0.27 for pathogenic). REVEL score 0.496 is borderline, just below the 0.5 pathogenic threshold. SpliceAI max delta 0.02 predicts no splicing impact. Multiple computational lines of evidence suggest no deleterious effect.

Recorded classification: Likely benign

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, BS2 supporting, BP4 supporting; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
4 reported laboratory submissions

3 Uncertain significance · 1 Benign. ClinVar API review status: criteria provided, conflicting classifications.

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
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 3 met · 19 not met · 0 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PM2 (supporting): This variant is absent from gnomAD v2.1 and present in gnomAD v4.1 at extremely low frequency (AF=0.000062%, 10/1,610,852 alleles, 0 homozygotes), well below the PM2 threshold of less than 0.1%.

BS2 (supporting): This variant is observed in 10 heterozygous individuals in gnomAD v4.1. TSC is a dominant disorder with near-complete penetrance and early childhood onset; observation in a population database of presumably healthy adults is inconsistent with a fully penetrant pathogenic variant.

BP4 (supporting): BayesDel score 0.161 is in the benign range. REVEL score 0.496 is borderline (just below 0.5 pathogenic threshold). SpliceAI max delta 0.02 predicts no splicing impact. Multiple computational lines of evidence suggest no deleterious effect.

PVS1 not applicable: Variant is a missense substitution (p.Pro341Leu), not a null variant eligible for PVS1 assessment.

PM1 not met: This variant does not lie in a statistically significant mutational hotspot per cancerhotspots.org.

PM5 not met: No same-residue pathogenic missense comparator variants were identified.

PS3 not met: No functional studies have been reported for this variant. OncoKB reports Unknown Oncogenic Effect.

PP3 not met: REVEL 0.496 is borderline; BayesDel 0.161 is benign; SpliceAI max delta 0.02 shows no splice impact. In silico tools do not converge on a damaging prediction.

PP5 not met: ClinVar review status is 1-star (criteria provided, single submitter), not 3-star expert panel. Classification is Uncertain significance with mixed submitters.

BP6 not met: ClinVar review status is 1-star, not 3-star expert panel. A single submitter classifies as Benign, insufficient for BP6.

No publications reviewed contained variant-specific evidence for NM_000368.4:c.1022C>T. All PMIDs are guideline/review papers that do not mention this variant.

Met · 3

PM2 SupportingThis variant is absent from gnomAD v2.1 and present in gnomAD v4.1 at extremely low frequency (AF=0.000062%, 10/1,610,852 alleles, 0 homozygotes), well below the PM2 threshold of less than 0.1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent. gnomAD v4.1: AF=6.2e-06 (0.00062%)
  • 10/1
  • 610
  • 852 alleles
  • 0 homozygotes
  • grpmax FAF=4.3e-06.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 SupportingThis variant is observed in 10 heterozygous individuals in gnomAD v4.1 (0 homozygotes). TSC is a dominant disorder with near-complete penetrance and early childhood onset. Observation in a population database of presumably healthy adults is inconsistent with a fully penetrant pathogenic variant, supporting a benign interpretation. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 10 heterozygous carriers
  • 0 homozygotes
  • all in European (non-Finnish) population. Total AN=1
  • 610
  • 852. TSC has near-complete penetrance with onset typically in infancy/early childhood.
Still missing
  • TSC can exhibit somatic mosaicism and variable expressivity
  • some gnomAD carriers could represent mildly affected or mosaic individuals.
Sources
gnomad_v4 ↗
BP4 SupportingBayesDel score 0.161 is in the benign range (threshold greater than 0.27 for pathogenic). REVEL score 0.496 is borderline, just below the 0.5 pathogenic threshold. SpliceAI max delta 0.02 predicts no splicing impact. Multiple computational lines of evidence suggest no deleterious effect. Details ▾Hide ▴
Evidence considered
  • BayesDel 0.161 (benign
  • below 0.27 pathogenic threshold). REVEL 0.496 (borderline-benign
  • below 0.5 threshold). SpliceAI max delta 0.02 (no splicing impact).
Sources
revelbayesdelspliceai ↗

Not met · 19 · evaluated, threshold not reached

PS2 No de novo occurrence (maternity and paternity confirmed) has been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo data available in ClinVar submissions
  • literature
  • or clinical records.
Still missing
  • If proband is known to have unaffected parents
  • confirmatory de novo testing could be pursued.
PS3 No functional studies have been reported for this variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. No publication describes experimental characterization of NM_000368.4:c.1022C>T or a systematically characterized range that includes this position. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no reviewed functional data. No variant-specific functional studies identified in literature search.
Still missing
  • Functional characterization of c.1022C>T (e.g.
  • TSC1-TSC2 binding assay
  • mTORC1 activity readout) would be required to assess PS3.
Sources
oncokb ↗
PS4 No case-control or cohort data demonstrate enrichment of this variant in affected individuals. No clinical case reports describe this variant in affected probands with TSC. Details ▾Hide ▴
Evidence considered
  • Variant is present in gnomAD v4.1 at extremely low frequency (10/1
  • 610
  • 852 alleles) with no case enrichment data. ClinVar contains no case counts or phenotype data.
Still missing
  • Case-control or cohort enrichment analysis in TSC patients vs. controls would be needed.
Sources
clinvar ↗gnomad_v4 ↗
PM1 This variant does not lie in a statistically significant mutational hotspot per cancerhotspots.org. Position 341 is not annotated within a well-characterized critical functional domain with absence of benign variation. Details ▾Hide ▴
Evidence considered
  • Cancerhotspots.org: residue not significant
  • exact variant not listed. No domain-level annotation confirming position 341 is in a critical functional domain without benign variation.
Still missing
  • Domain-level structural/functional annotation for TSC1 position 341 would be needed.
PM5 No same-residue pathogenic missense comparator variants were identified in automated PM5 candidate harvesting. Details ▾Hide ▴
Evidence considered
  • PM5 candidate review found 0 same-residue comparator variants. No ClinVar pathogenic missense variant at position 341.
Still missing
  • Manual ClinVar review for same-residue pathogenic missense variants at Pro341 could be considered.
Sources
pm5_candidates
PM6 No de novo observation (maternity and paternity unconfirmed) has been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo data with unconfirmed parentage available.
Still missing
  • If proband is known to have unaffected parents
  • PM6 could be evaluated with unconfirmed maternity/paternity.
PP1 No co-segregation data available. No family studies have been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No family segregation data identified in literature or ClinVar submissions.
Still missing
  • Family segregation analysis would be required if additional affected/unaffected relatives are available for testing.
PP2 No missense constraint data (z-score) was available to confirm TSC1 has a low rate of benign missense variation where missense is a common disease mechanism. Details ▾Hide ▴
Evidence considered
  • HCI prior not available for TSC1. gnomAD missense constraint metrics not assessed.
Still missing
  • gnomAD missense z-score or other constraint metric for TSC1 would be required to assess PP2.
PP3 REVEL score 0.496 is borderline/equivocal, BayesDel score 0.161 is in the benign range, and SpliceAI max delta is 0.02 (no splice impact). Multiple in silico tools do not converge on a damaging prediction. Details ▾Hide ▴
Evidence considered
  • REVEL 0.496 (borderline
  • just below common 0.5 pathogenic threshold). BayesDel 0.161 (benign
  • below 0.27 pathogenic threshold). SpliceAI max delta 0.02 (no splicing impact). No HCI prior available.
Sources
revelbayesdelspliceai ↗
PP4 No patient phenotype or family history information was provided for assessment of phenotypic specificity. Details ▾Hide ▴
Evidence considered
  • No proband phenotype data available.
Still missing
  • Proband phenotype details would be required to assess PP4 for TSC-specific features.
PP5 ClinVar review status is 'criteria provided, single submitter' (1-star), not 3-star expert panel. Classification is uncertain significance with 3 submitters and benign with 1 submitter. PP5 requires a 3-star expert panel classification as Pathogenic/Likely Pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar VCV000659997: Uncertain significance (3 clinical laboratories)
  • Benign (1). Review status: criteria provided
  • single submitter (1-star). No expert panel review.
Sources
clinvar ↗
BA1 gnomAD v4.1 allele frequency is 0.000062%, far below the BA1 threshold of greater than 1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: AF=6.2e-06 (0.00062%)
  • 10/1
  • 610
  • 852 alleles.
Sources
gnomad_v4 ↗
BS1 gnomAD v4.1 allele frequency is 0.000062%, below the BS1 threshold of greater than 0.3%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: AF=6.2e-06 (0.00062%)
  • 10/1
  • 610
  • 852 alleles.
Sources
gnomad_v4 ↗
BS3 No functional studies demonstrating no deleterious effect have been reported for this variant. OncoKB reports Unknown Oncogenic Effect. Details ▾Hide ▴
Evidence considered
  • No variant-specific functional evidence demonstrating normal TSC1 function for c.1022C>T.
Still missing
  • Functional assays demonstrating wild-type TSC1 activity for p.Pro341Leu would be required.
Sources
oncokb ↗
BS4 No non-segregation data available for this variant. Details ▾Hide ▴
Evidence considered
  • No family studies demonstrating lack of segregation with disease.
Still missing
  • Family testing demonstrating absence of the variant in affected relatives would be required.
BP1 Although TSC1 loss of function is a known disease mechanism, both truncating and missense pathogenic variants are well-documented in TSC1. The variant spectrum does not support that primarily truncating variants cause disease to the exclusion of missense. Details ▾Hide ▴
Evidence considered
  • TSC1 LOF mechanism is well-established
  • but pathogenic missense variants are also documented in ClinVar for TSC1.
Sources
pvs1_gene_context
BP2 No observation in trans with a pathogenic variant has been reported for this dominant disorder. Details ▾Hide ▴
Evidence considered
  • No trans configuration data available.
BP5 No alternative molecular basis for disease has been identified that would explain the phenotype independent of this variant. Details ▾Hide ▴
Evidence considered
  • No alternative pathogenic variant identified in case data.
Still missing
  • If another pathogenic variant in TSC1 or a different gene explains the phenotype
  • BP5 could be applied.
BP6 ClinVar review status is 'criteria provided, single submitter' (1-star), not 3-star expert panel. A single submitter classified as Benign. BP6 requires a 3-star expert panel classification as Benign/Likely Benign. Details ▾Hide ▴
Evidence considered
  • ClinVar VCV000659997: 1 submitter classifies as Benign with criteria provided
  • single submitter (1-star). Insufficient for BP6.
Sources
clinvar ↗
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AVariant is a missense substitution (p.Pro341Leu), not a null variant (nonsense, frameshift, or canonical splice). The generic PVS1 framework does not apply to missense variants. Details ▾Hide ▴
Evidence considered
  • Variant class is 'other' (missense)
  • not eligible for generic PVS1 decision tree per ClinGen SVI PVS1 recommendations (PMC6185798).
Sources
pvs1_variant_assessment
PS1 N/ANo other nucleotide change at the same position has been reported as pathogenic to produce the same amino acid change (Pro341Leu). Details ▾Hide ▴
Evidence considered
  • No alternate nucleotide substitution at c.1022 yielding the same protein change is documented in ClinVar or the literature.
BP7 N/AVariant is a missense substitution (c.1022C>T, p.Pro341Leu), not a synonymous/silent variant. BP7 applies only to synonymous variants without predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Variant type: missense. BP7 criteria are specific to synonymous variants.
PS5 N/ANot a standard ACMG/AMP 2015 criterion. No applicable evidence identified. Details ▾Hide ▴
Evidence considered
  • No evidence applicable to any extended PS5 definition.

Identifiers

Gene
TSC1
Transcript
NM_000368.4
Coding (HGVS c.)
NM_000368.4:c.1022C>T
Protein (HGVS p.)
NP_000359.1:p.(Pro341Leu)
GRCh38
chr9:132911460 G>A
GRCh37
chr9:135786847 G>A
ClinVar
659997

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…
gnomAD v4.1 10 / 1,610,852 alleles AF 6.21e-06 · 0 homozygotes · FAF 4.3e-06
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.2e-06 · 10 / 1,610,852 alleles · 0 hom · FAF 4.3e-06
European (non-Finnish)10 / 1,177,170 8.5e-06
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.20789e-06; MAF= 0.00062%, 10/1610852 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.49495e-06; MAF= 0.00085%, 10/1177170 alleles, homozygotes = 0); grpmax FAF= 4.3e-06.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -347 bp
0.010
SpliceAI acceptor gainat +360 bp
0.000
SpliceAI donor lossat -68 bp
0.000
SpliceAI donor gainat -7 bp
0.020
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.050

Other predictors

REVEL
0.496
BayesDel
0.161

How the predictions were used

BP4 SupportingBayesDel score 0.161 is in the benign range (threshold greater than 0.27 for pathogenic). REVEL score 0.496 is borderline, just below the 0.5 pathogenic threshold. SpliceAI max delta 0.02 predicts no splicing impact. Multiple computational lines of evidence suggest no deleterious effect. Details ▾Hide ▴
Evidence considered
  • BayesDel 0.161 (benign
  • below 0.27 pathogenic threshold). REVEL 0.496 (borderline-benign
  • below 0.5 threshold). SpliceAI max delta 0.02 (no splicing impact).
Sources
revelbayesdelspliceai ↗
PP3 REVEL score 0.496 is borderline/equivocal, BayesDel score 0.161 is in the benign range, and SpliceAI max delta is 0.02 (no splice impact). Multiple in silico tools do not converge on a damaging prediction. Details ▾Hide ▴
Evidence considered
  • REVEL 0.496 (borderline
  • just below common 0.5 pathogenic threshold). BayesDel 0.161 (benign
  • below 0.27 pathogenic threshold). SpliceAI max delta 0.02 (no splicing impact). No HCI prior available.
Sources
revelbayesdelspliceai ↗
BP7 N/AVariant is a missense substitution (c.1022C>T, p.Pro341Leu), not a synonymous/silent variant. BP7 applies only to synonymous variants without predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Variant type: missense. BP7 criteria are specific to synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.496. BayesDel score = 0.161359.

7 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

  • 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.
    Richards S et al. · 2015
    ACMG/AMP standards and guidelines for the interpretation of sequence variants. NM_000368.4:c.1022C>T was not identified in this paper.
    Does not name this variant
    PMID 25741868 ↗
  • Tuberous Sclerosis Complex.
    Adam MP et al. · 1993
    GeneReviews chapter on Tuberous Sclerosis Complex. NM_000368.4:c.1022C>T was not identified in the abstract or available content.
    Does not name this variant
    PMID 20301399 ↗
  • Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions.
    Schaefer GB et al. · 2013
    ACMG practice guideline on clinical genetics evaluation for autism spectrum disorders. NM_000368.4:c.1022C>T was not identified in this paper.
    Does not name this variant
    PMID 23519317 ↗
  • ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
    Green RC et al. · 2013
    ACMG recommendations for reporting incidental findings in clinical exome and genome sequencing. NM_000368.4:c.1022C>T was not identified in this paper.
    Does not name this variant
    PMID 23788249 ↗
  • 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. · 2015
    ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. NM_000368.4:c.1022C>T was not identified in this paper.
    Does not name this variant
    PMID 25394175 ↗
  • 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. · 2017
    ACMG recommendations for reporting secondary findings in clinical exome and genome sequencing (2016 update, SF v2.0). NM_000368.4:c.1022C>T was not identified in this paper.
    Does not name this variant
    PMID 27854360 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. NM_000368.4:c.1022C>T was not identified in the abstract or available content.
    Does not name this variant
    PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 10 / 1,610,852 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.020 Open source ↗
ClinVar 3 Uncertain significance · 1 Benign 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

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.20789e-06; MAF= 0.00062%, 10/1610852 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.49495e-06; MAF= 0.00085%, 10/1177170 alleles, homozygotes = 0); grpmax FAF= 4.3e-06.

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 (3 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 659997)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.496. BayesDel score = 0.161359.

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.