NM_000548.4:c.3581G>T (p.Trp1194Leu) is a missense variant in TSC2, a gene in which loss-of-function is an established mechanism for autosomal dominant tuberous sclerosis complex.1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.2 In silico predictors support a deleterious effect: REVEL score 0.89 and BayesDel score 0.518, meeting PP3 at supporting strength. SpliceAI predicts no aberrant splicing (max delta 0.02).3 No pathogenic (PVS1, PS1-PS5) or benign (BA1, BS1-BS4) criteria are met beyond PM2_supporting and PP3_supporting.4 Under generic ACMG/AMP 2015 combination rules (PMID:25741868), two supporting pathogenic criteria (PM2 + PP3) without any moderate or strong criteria is insufficient for Likely Pathogenic and results in a final classification of Variant of Uncertain Significance (VUS).5
TSC2
Final classification
VUS
TSC2 c.3581G>T · p.Trp1194Leu
TSC2
NM_000548.4:c.3581G>T (p.Trp1194Leu) is a missense variant in TSC2, a gene in which loss-of-function is an established mechanism for autosomal dominant tuberous sclerosis complex.
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, PP3 supporting; combination = 2 supporting, which maps to VUS.
Classification rationale
PM2PP3
VUS
TSC2 c.3581G>T
PM2 + PP3
→
VUS
1
pvs1_gene_contextgeneric_acmg_combination_rules
3
revelbayesdelspliceai ↗
4
clinvar ↗pm5_candidates
5
generic_acmg_combination_rules
Gene diagram
· NM_000548.4 · variants mapped to exon structure
TSC2
NM_000548.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
Variant is absent from gnomAD v2.1 (0 alleles), gnomAD v4.1 (0 alleles), and gnomAD-Canada v1.0 (0 alleles), meeting the <0.1% allele frequency threshold for PM2 under the generic ACMG/AMP framework.
Absent from gnomAD v2.1 (0/0 alleles)absent from gnomAD v4.1 (0/0 alleles)absent from gnomAD-Canada v1.0 (0/0 alleles).
✓
PP3
supporting
Pathogenic
Multiple in silico tools predict a deleterious effect: REVEL score 0.89 (high-confidence damaging range, threshold >0.5), BayesDel score 0.518 (above deleterious threshold). SpliceAI predicts no splicing impact (max delta 0.02), which is expected for a missense variant and does not negate the protein-level predictions.
REVEL 0.89 (deleterious)BayesDel 0.517806 (deleterious)SpliceAI max delta 0.02 (no splicing impact — consistent with missense mechanism).
Assessed · not applied
Pathogenic
PS2
No de novo occurrence with confirmed paternity and maternity has been reported for this variant in population databases or the literature.
PS3
No variant-specific functional studies identified.
PS4
Variant is absent from gnomAD v2.1 and v4.1; no case-control data available to demonstrate statistically significant enrichment in affected individuals versus controls.
PM1
Residue 1194 lies between the N-terminal hamartin-binding domain and the C-terminal GAP domain of tuberin.
PM6
No report of this variant occurring as an assumed de novo event (without confirmation of paternity and maternity).
PP1
No cosegregation data available.
PP2
HCI prior score not available for TSC2.
PP4
No patient phenotype or family history data available for this variant.
PP5
No reputable source reports this variant as pathogenic.
Benign
BA1
Variant is absent from gnomAD v2.1 and v4.1; allele frequency is far below the >1% threshold for BA1.
BS1
Variant is absent from gnomAD v2.1 and v4.1; allele frequency is far below the >0.3% threshold for BS1 under generic ACMG.
BS2
No observation of this variant in a healthy adult individual where full penetrance would be expected at an early age.
BS3
No well-established in vitro or in vivo functional studies demonstrate a neutral or normal effect of p.Trp1194Leu on protein function.
BS4
No segregation data available to demonstrate lack of cosegregation with disease in affected family members.
BP1
Tuberous sclerosis complex is caused by both truncating and missense pathogenic variants in TSC2.
BP2
No observation of this variant in trans with a known pathogenic TSC2 variant in an unaffected individual.
BP4
Multiple in silico tools predict a deleterious effect, not a benign one: REVEL 0.89 (damaging), BayesDel 0.518 (deleterious).
BP5
No observation of this variant in a case where an alternate molecular basis for disease was identified.
BP6
No reputable source reports this variant as benign.
N/A · 4
PVS1 · PS1 · 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
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.89. BayesDel score = 0.517806.
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. TSC2, a GTPase-activating protein, is altered by mutation in various cancers, including endometrial and colorectal cancer.
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.
Sources & reference links
Triaged references · 8 PMIDs not cited in assessment
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
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
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