TSC1

Final classification

VUS

TSC1 c.1801C>A · p.Pro601Thr

TSC1

Gene

TSC1

Transcript

NM_000368.4

HGVS · transcript:coding

NM_000368.4:c.1801C>A

Consequence

N/A

GRCh38

chr9:132905777 G>T

GRCh37

chr9:135781164 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, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, 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, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.

Classification rationale

PM2 BP4 VUS

TSC1 c.1801C>A

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).¹ 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.² ClinVar classifies this variant as Uncertain Significance (criteria provided, single submitter, 2 clinical laboratories); no expert panel classification is available.³ 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.⁴

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 revelbayesdelspliceai ↗

3 clinvar ↗

4 generic_acmg_combination_rules

Gene diagram · NM_000368.4 · variants mapped to exon structure

TSC1 NM_000368.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 20 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

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%.

gnomAD v2.1: absent (0 alleles).gnomAD v4.1: absent (0 alleles).gnomAD-Canada v1.0: absent (0 alleles).

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

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.

BayesDel: -0.201 (benign prediction).SpliceAI max delta: 0.02 (no splice impact).REVEL: 0.453 (indeterminate

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No known pathogenic missense variant at the same amino acid residue (Pro601) with a different amino acid change was identified.

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.

PS3 No variant-specific functional studies have been reported.

PS4 Variant is absent from gnomAD but no case-control or statistical enrichment evidence in affected individuals has been reported.

PM1 Variant does not lie in a statistically significant mutational hotspot; hotspot analysis negative.

PM6 No de novo observation has been reported for this variant.

PP1 No segregation data have been reported for this variant.

PP2 PP2 is applied when a gene has a low rate of benign missense variation and missense variants are a common disease mechanism.

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).

PP4 No patient phenotype data are available for this specific variant.

PP5 ClinVar classification is Uncertain Significance (criteria provided, single submitter, 2 clinical laboratories).

Benign

BA1 Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.

BS1 Variant is absent from gnomAD.

BS2 Variant is absent from gnomAD; no evidence of observation in healthy adults.

BS3 No functional studies have been reported demonstrating a neutral or benign effect for this variant.

BS4 No segregation data demonstrating non-segregation with disease are available.

BP1 BP1 applies to missense variants in genes where only truncating variants cause disease.

BP2 No evidence of observation in trans with a known pathogenic variant for this fully penetrant autosomal dominant disorder.

BP5 No evidence that an alternative molecular basis explains disease in any case where this variant was observed.

BP6 ClinVar classification is Uncertain Significance, not Benign or Likely Benign.

N/A · 3 PVS1 · PM5 · BP7

Research & evidence

Population frequency

gnomAD v4.1

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

Error retrieving ClinVar entry.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.453. BayesDel score = -0.200853.

SpliceAI ↗

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. TSC1, a scaffold protein, is frequently altered by mutation in bladder cancer.

OncoKB ↗

COSMIC

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 · 6 PMIDs not cited in assessment

23519317 ↗ Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. CLINVAR

25356965 ↗ ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. CLINVAR

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. 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

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