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NM_000548.5:c.3834G>A
p.Leu1278= · TSC2
ACMG/AMP
0%
complete
Final classification
VUS
PM2BP7
TSC2
c.3834G>A
p.Leu1278=
synonymous · exon 32
Gene context NCBI Gene ↗ OncoKB ↗

TSC2 is a tumor suppressor gene that encodes tuberin, a growth-inhibitory protein. Tuberin teams up with hamartin to form the TSC protein complex, which keeps cell growth in check by dampening mTORC1 signaling. Mutations in TSC2 cause tuberous sclerosis, a disorder featuring benign and occasionally malignant tumors, and are also linked to lymphangioleiomyomatosis. Loss-of-function changes in TSC2 are seen in some cancers, such as liver and endometrial cancers, and can make tumors sensitive to mTOR-inhibiting drugs.

This variant

TSC2 encodes tuberin, which partners with hamartin to restrain mTORC1 signaling, and loss-of-function changes cause autosomal-dominant tuberous sclerosis complex and can contribute to lymphangioleiomyomatosis and cancer biology.

Transcript
NM_000548.5
HGVS · transcript:coding
NM_000548.5:c.3834G>A
GRCh38
chr16:2082455 G>A
GRCh37
chr16:2132456 G>A
VUS: PM2 (supporting) and BP7 (supporting) do not satisfy generic ACMG/AMP thresholds for a pathogenic, likely pathogenic, likely benign, or benign call.
Classification rationale
PM2 BP7 VUS
TSC2 c.3834G>A synonymous · exon 32

PM2 supporting: the gnomAD v4.1 allele frequency is 6.20159e-07, below the generic supporting threshold of 0.0001. BP7 supporting: the synonymous variant has a SpliceAI maximum delta of 0.112, below the 0.2 threshold for significant predicted splice impact.

PM2 + BP7 → VUS
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.
Gene diagram · NM_000548.5 · variants mapped to exon structure
TSC2 NM_000548.5
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 15 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength Supporting Moderate Strong Very strong
PM2 supporting Pathogenic
Met at supporting strength: gnomAD v4.1 allele frequency is 6.20159e-07, below the generic PM2 threshold of 0.0001.
gnomAD v2.1 all-comers exomes: AF 7.9915e-06, 2/250266 alleles, and 0 homozygotes; maximum ancestry-specific AF 1.77016e-05.gnomAD v2.1 non-cancer exomes: AF 4.2259e-06, 1/236636 alleles, and 0 homozygotes.gnomAD v4.1: AF 6.20159e-07, 1/1612490 alleles, and 0 homozygotes.
gnomad_v2 ↗gnomad_v4 ↗
BP7 supporting Benign
Met, supporting: synonymous c.3834G>A has SpliceAI max delta 0.112, below the 0.2 significant-impact cutoff.
The variant is synonymous: NM_000548.5:c.3834G>A, NP_000539.2:p.(Leu1278=).SpliceAI scores are DS_AG 0.067, DS_AL 0.112, DS_DG 0.002, and DS_DL 0.073; maximum delta score is 0.112.SpliceAI recommended cutoff for significant splice impact is 0.2, from Jaganathan et al. 2019 (PMID:30661751); max delta 0.112 is below this cutoff and supports BP7's no-predicted-splicing-impact requirement.
spliceai ↗
Assessed · not applied · 5 not met · 10 not assessed
Pathogenic
PS2 Not assessed: parental genotypes and confirmed maternity/paternity are not documented for this variant.
PS3 Not assessed: no variant-specific validated functional assay or disease-relevant abnormality is available for c.3834G>A (p.Leu1278=).
PS4 Not assessed: no variant-specific affected-versus-control counts or enrichment statistic were available for PS4.
PM6 Not assessed: presumed de novo status, parental testing, and a consistent proband phenotype are not documented.
PP1 Not assessed: no affected relatives, informative meioses, or genotype–phenotype segregation data are available.
PP4 Not assessed: no patient phenotype or family history was provided to evaluate specificity for tuberous sclerosis complex.
PP5 Not met: the exact ClinVar variant has zero expert-panel submissions and no Pathogenic or Likely pathogenic expert-panel classification.
Benign
BA1 Not met: the highest observed allele frequency is 1.77016e-05, far below the generic BA1 threshold of 0.05.
BS1 Not met: the highest observed allele frequency is 1.77016e-05, below the generic BS1 threshold of 0.01.
BS2 Not met: gnomAD reports 0 homozygotes and only rare heterozygotes, without phenotype-confirmed healthy individuals establishing BS2.
BS3 Not assessed: no variant-specific validated assay demonstrates normal function for c.3834G>A (p.Leu1278=).
BS4 Not assessed: no tested unaffected relatives or reliable non-segregation observations are documented.
BP2 Not assessed: no second pathogenic variant or cis/trans phase result is documented for NM_000548.5:c.3834G>A.
BP5 Not assessed: no patient phenotype or alternate pathogenic molecular diagnosis was provided to establish another cause.
BP6 Not met: the exact ClinVar Likely benign assertion is from a single laboratory, while zero expert-panel submissions are recorded.
N/A · 11 PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP4
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.20159e-07; MAF= 0.00006%, 1/1612490 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47453e-07; MAF= 0.00008%, 1/1180006 alleles, homozygotes = 0).
v2.1
This variant is present in gnomAD v2.1 (AF= 7.9915e-06; MAF= 0.00080%, 2/250266 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.77016e-05; MAF= 0.00177%, 2/112984 alleles, homozygotes = 0); grpmax FAF= 2.94e-06.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05% · 1 / 1,612,490
0 hom
European (non-Finnish)
1 / 1,180,006
8.5e-05%
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0008% · 2 / 250,266
0 hom · FAF 0.00029%
European (non-Finnish)
2 / 112,984
0.0018%
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 735798)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11).
SpliceAI ↗
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
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
20301399 ↗ Tuberous Sclerosis Complex. CLINVAR
23788249 ↗ ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. CLINVAR
25356965 ↗ ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. 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
34012068 ↗ ACMG SF v3.0 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