Classification rationale

PM2 BP4 VUS

TSC1 c.3106G>A

PM2 (supporting): This variant is extremely rare in population databases — absent from gnomAD v2.1, present in gnomAD v4.1 at an allele frequency of 6.2e-7 (1/1,613,770 alleles, no homozygotes), and absent from gnomAD-Canada.¹ BP4 (supporting): Two in silico predictors suggest no deleterious impact — BayesDel score -0.172 (benign) and SpliceAI max delta 0.00 (no splice alteration). REVEL score 0.291 is indeterminate and does not override.² PM2 (supporting) and BP4 (supporting) cancel each other, yielding no net evidence for or against pathogenicity. The variant remains a Variant of Uncertain Significance.

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 revelbayesdelspliceai ↗

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

TSC1 NM_000368.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 21 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

This variant is extremely rare in population databases: absent from gnomAD v2.1 and gnomAD-Canada, and present in gnomAD v4.1 at an allele frequency of 6.2e-7 (1/1,613,770 alleles, 0 homozygotes), well below the 0.1% PM2 threshold.

gnomAD v2.1: absentgnomAD v4.1: AF = 6.2e-7 (1/1613

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Two independent in silico predictors suggest no deleterious impact: BayesDel score -0.172 is in the benign range (<0.0) and SpliceAI max delta 0.00 predicts no splice alteration. REVEL score 0.291 falls in the indeterminate range but does not contradict the benign predictions.

BayesDel: -0.172 (benign)SpliceAI: max delta = 0.00 (no splicing impact predicted)REVEL: 0.291 (indeterminate

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No known pathogenic variant at codon 1036 with a different nucleotide change producing the same amino acid change (p.Gly1036Arg).

PS2 No de novo observation with confirmed maternity and paternity identified for this variant in the reviewed literature.

PS3 No variant-specific functional studies identified.

PS4 No case-control studies or cohort data demonstrating statistically significant enrichment of this variant in affected individuals relative to controls.

PM1 Not located in a statistically significant mutational hotspot per cancerhotspots.org.

PM5 No same-residue comparator variant identified.

PM6 No de novo observation reported for this variant in the reviewed literature.

PP1 No co-segregation data available.

PP2 Insufficient data to determine whether TSC1 has a low rate of benign missense variation and whether missense variants are a common disease mechanism.

PP3 Multiple in silico tools do not support a deleterious effect: REVEL score 0.291 is in the indeterminate range (neither benign <0.25 nor pathogenic >0.5), BayesDel score -0.172 is in the benign range (<0.0), and SpliceAI max delta 0.00 predicts no splice impact.

PP4 No patient-specific clinical phenotype or family history data provided for this variant.

PP5 ClinVar classification for this variant is Uncertain Significance (3 submitters) with review status 'criteria provided, single submitter' (1-star).

Benign

BA1 Allele frequency in gnomAD v4.1 is 6.2e-7 (0.00006%), well below the 1% BA1 threshold.

BS1 Allele frequency in gnomAD v4.1 is 6.2e-7 (0.00006%), well below the 0.3% BS1 threshold.

BS2 Only 1 allele observed among >1.6 million alleles in gnomAD v4.1, with 0 homozygotes.

BS3 No variant-specific functional studies demonstrating a benign effect.

BS4 No non-segregation data available.

BP1 While truncating variants in TSC1 cause tuberous sclerosis complex, missense variants are also a recognized disease mechanism in TSC1 (e.g., disrupting the TSC1-TSC2 interaction).

BP2 No observation of this variant in trans with a known pathogenic TSC1 variant.

BP5 No observation of this variant in a case with an alternate molecular basis for disease.

BP6 ClinVar classification for this variant is Uncertain Significance (3 submitters), not benign or likely benign.

N/A · 5 PVS1 · PM3 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.19667e-07; MAF= 0.00006%, 1/1613770 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33301e-05; MAF= 0.00133%, 1/75018 alleles, homozygotes = 0).

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

6.2e-05% · 1 / 1,613,770
0 hom

African/African American

1 / 75,018

0.0013%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish))

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

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 663161)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.291. BayesDel score = -0.172488.

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

25741868 ↗ 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. CLINVAR

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

23788249 ↗ ACMG recommendations for reporting of incidental findings in clinical exome and genome 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