Classification rationale

BS1BS2 Benign

TSC1 c.2865C>T

BS1 (Strong): allele frequency ~0.3% in gnomAD exceeds the ~0.006% maximum credible TSC1 disease-allele frequency by ~40-50x. BS2 (Strong): 10 homozygotes in gnomAD v4.1 for a fully penetrant, early-onset autosomal dominant disorder. Benign: two strong benign criteria (BS1 + BS2) under the generic ACMG/AMP 2015 combination rule.

BS1 + BS2 → Benign

Gene diagram · NM_000368.5 · variants mapped to exon structure

TSC1 NM_000368.5

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 17 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

BS1 strong Benign

Met (Strong): allele frequency ~0.3% exceeds the maximum credible TSC1 disease-allele frequency (~0.006%) by ~40-50x.

gnomAD v4.1 (source: gnomad_v4): NFE AF 0.003161 (3730/1180034 alleles), grpmax FAF 0.003076 - exceeds maximum credible disease-allele AF for TSC1 (~0.00006, i.e. ~0.006%) by ~50xgnomAD v2.1 (source: gnomad_v2): NFE AF 0.002849 (368/129158), grpmax FAF 0.002993 - exceeds maximum credible TSC1 disease-allele AF by ~45xMaximum credible allele frequency approach (Whiffin et al. 2017, Genet Med 19(10):1151-1158, PMID:28518168): AF_max for a single TSC1 pathogenic allele estimated from TSC prevalence ~1/6,000-1/10,000 (autosomal dominant, near-full penetrance) and TSC1 causal fraction ~1/3, giving AF_max ~0.006% or less

gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗clinvar ↗

✓

BS2 strong Benign

Met (Strong): 10 homozygotes in gnomAD v4.1 are incompatible with a fully penetrant, early-onset dominant disorder.

gnomAD v4.1 (source: gnomad_v4): total homozygotes = 10 (9 NFE, 1 AMR; exome 8, genome 2) among 1,614,154 alleles - homozygous observation in a general population cohort for a fully penetrant dominant disordergnomAD v2.1 (source: gnomad_v2): total homozygotes = 1 (NFE exome) among 282,842 allelesgnomAD-Canada v1.0 (source: gnomad_canada): 0 homozygotes (24/18420 alleles) - no contradiction

gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗clinvar ↗

Assessed · not applied

Pathogenic

PS2 Not assessed: no de novo occurrence with confirmed parentage is reported for this variant.

PS3 Not assessed: no well-established functional study of this variant was available.

PS4 Not met: the variant is a common polymorphism (gnomAD AF 0.17-0.25%) with no case-control enrichment evidence.

PM2 Not met: allele frequency 0.25% (gnomAD v4.1) far exceeds the 0.1% rarity threshold.

PM6 Not assessed: no de novo occurrence, with or without confirmed parentage, is reported.

PP1 Not assessed: no segregation data in affected family members was available.

PP3 Not met: SpliceAI max delta 0.17 is below the 0.20 splice-altering threshold, so no splice impact is predicted.

PP4 Not assessed: no proband phenotype or family-history data was available.

PP5 Not met: no ClinVar expert panel has classified this variant as pathogenic (aggregate is Benign/Likely benign).

Benign

BA1 Not met: highest allele frequency 0.32% (gnomAD v4.1 NFE) is well below the 5% threshold.

BS3 Not assessed: no well-established functional study showing no damaging effect was available.

BS4 Not assessed: no data on affected relatives lacking the variant was available.

BP2 Not assessed: no cis/trans phase data against a pathogenic variant is available.

BP4 Not met: only one independent computational no-impact line (SpliceAI) exists, short of the multiple-line requirement.

BP5 Not assessed: no case-level data showing an alternative molecular cause in a carrier was available.

BP6 Not met: the ClinVar benign label comes from routine laboratory submissions, not an expert panel.

BP7 Not assessed: conservation data (phyloP/GERP) was unavailable to complete the synonymous/splice-neutral check; flagged for human review.

N/A · 9 PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.00252516; MAF= 0.25252%, 4076/1614154 alleles, homozygotes = 10) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00316093; MAF= 0.31609%, 3730/1180034 alleles, homozygotes = 9); grpmax FAF= 0.00307583.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.00166878; MAF= 0.16688%, 472/282842 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00284922; MAF= 0.28492%, 368/129158 alleles, homozygotes = 1); grpmax FAF= 0.00299349.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.0013029315960912053, 24/18420 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.25% · 4076 / 1,614,154
10 hom · FAF 0.31%

European (non-Finnish) 3730 / 1,180,034	0.32% 9 hom
Remaining individuals 129 / 62,512	0.21%
South Asian 107 / 91,078	0.12%
Admixed American 60 / 60,028	0.1% 1 hom
African/African American 42 / 75,010	0.056%
Middle Eastern 1 / 6,062	0.016%
European (Finnish) 6 / 64,024	0.0094%
Ashkenazi Jewish 1 / 29,608	0.0034%

+ 2 not observed (Amish, East Asian)

gnomAD v2.1

0.17% · 472 / 282,842
1 hom · FAF 0.3%

European (non-Finnish) 368 / 129,158	0.28% 1 hom
South Asian 39 / 30,616	0.13%
Remaining individuals 7 / 7,224	0.097%
Admixed American 33 / 35,440	0.093%
African/African American 19 / 24,962	0.076%
European (Finnish) 5 / 25,118	0.02%
Ashkenazi Jewish 1 / 10,370	0.0096%

+ 1 not observed (East Asian)

gnomAD Canada 🇨🇦

0.13% · 24 / 18,420
0 hom · FAF 0.13%

European (non-Finnish) 22 / 11,740	0.19%
Remaining individuals 1 / 1,138	0.088%
South Asian 1 / 1,362	0.073%

+ 6 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (17 clinical laboratories) and as Likely benign (6 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as benign (1 clinical laboratory). (ClinVarID = 49008)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.17).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104404429, n = 5 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 8 further PMIDs triaged but not cited — see Sources & References.

Rule & framework references · cited for criterion definitions, not variant evidence

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.

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

15798777 ↗ Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype--phenotype correlations and comparison of diagnostic DNA techniques in Tuberous Sclerosis Complex. CLINVAR

24033266 ↗ A systematic approach to assessing the clinical significance of genetic variants. CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

10533067 ↗ Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis. CLINVAR

20301399 ↗ Tuberous Sclerosis Complex. 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

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR