NM_000548.4:c.3581G>T

TSC2 · NP_000539.2:p.(Trp1194Leu) · NM_000548.4

GRCh37: chr16:2130349 G>T · GRCh38: chr16:2080348 G>T

Gene: TSC2 Transcript: NM_000548.4

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

TSC2

Transcript

NM_000548.4

Protein

NP_000539.2:p.(Trp1194Leu)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.

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).

No pathogenic (PVS1, PS1-PS5) or benign (BA1, BS1-BS4) criteria are met beyond PM2_supporting and PP3_supporting.

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Missense variant (p.Trp1194Leu); does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Apply_generic_pvs1_framework is false per pvs1_variant_assessment.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	Tryptophan at position 1194 is encoded only by TGG. No alternate nucleotide change at this codon can produce the same W1194L missense change, so no comparator variant with the same amino acid change exists.
PS2	Not met	No de novo occurrence with confirmed paternity and maternity has been reported for this variant in population databases or the literature.	clinvar
PS3	Not met	No variant-specific functional studies identified. REVEL score of 0.89 and BayesDel score of 0.518 are in silico predictions, not well-established functional assays per ACMG/AMP guidelines. OncoKB reports unknown oncogenic effect with no curated functional evidence for this variant.	revel bayesdel oncokb
PS4	Not met	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. ClinVar contains a single VUS submission with no proband counts.	gnomad_v2 gnomad_v4 clinvar
PS5	Not met	No reputable source reports this variant as pathogenic. ClinVar classification is Uncertain Significance from a single submitter (criteria provided, single submitter review status). The eight ClinVar-associated PMIDs are general guideline or review articles that do not address this specific variant.	clinvar
PM1	Not met	Residue 1194 lies between the N-terminal hamartin-binding domain and the C-terminal GAP domain of tuberin. No statistically significant mutational hotspot has been identified at this position, and the variant is not located in a critical or well-established functional domain without benign variation.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No pathogenic missense variant identified at the same amino acid residue (Trp1194) to serve as a comparator. pm5_candidates.json confirms zero same-residue candidates; eligible_for_classic_pm5_search is false.	pm5_candidates
PM6	Not met	No report of this variant occurring as an assumed de novo event (without confirmation of paternity and maternity). Not identified in LOVD, ClinVar, or the literature as a de novo observation.	clinvar
PP1	Not met	No cosegregation data available. No families with this variant and multiple affected members have been reported in databases or the literature.
PP2	Not assessed	HCI prior score not available for TSC2. Cannot determine whether the gene has a low rate of benign missense variation to satisfy PP2 criteria. This criterion requires evidence that missense variants are a common mechanism of disease and that benign missense variation is rare in the gene.
PP3	Met	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 bayesdel spliceai
PP4	Not met	No patient phenotype or family history data available for this variant. Cannot assess whether the proband's clinical presentation is highly specific for TSC2-related tuberous sclerosis complex.
PP5	Not met	No reputable source reports this variant as pathogenic. ClinVar classification is VUS (criteria provided, single submitter). All eight ClinVar-associated PMIDs are general guideline or review articles (GeneReviews chapter, ACMG secondary findings policies, Sherloc criteria) that do not address this specific variant.	clinvar
BA1	Not met	Variant is absent from gnomAD v2.1 and v4.1; allele frequency is far below the >1% threshold for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	Variant is absent from gnomAD v2.1 and v4.1; allele frequency is far below the >0.3% threshold for BS1 under generic ACMG.	gnomad_v2 gnomad_v4
BS2	Not met	No observation of this variant in a healthy adult individual where full penetrance would be expected at an early age. TSC2-related disease typically manifests in childhood; observation in an unaffected adult could support BS2, but no such observation exists.
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate a neutral or normal effect of p.Trp1194Leu on protein function. No functional data exist for this variant.
BS4	Not met	No segregation data available to demonstrate lack of cosegregation with disease in affected family members. No families with this variant have been reported.
BP1	Not met	Tuberous sclerosis complex is caused by both truncating and missense pathogenic variants in TSC2. Missense variants are an established disease mechanism in this gene, so BP1 (missense variant in a gene where only truncating variants cause disease) does not apply.	pvs1_gene_context
BP2	Not met	No observation of this variant in trans with a known pathogenic TSC2 variant in an unaffected individual. TSC2-related disease is autosomal dominant with full penetrance expected at an early age, so an observation in trans in a healthy individual would support BP2, but no such observation exists.
BP4	Not met	Multiple in silico tools predict a deleterious effect, not a benign one: REVEL 0.89 (damaging), BayesDel 0.518 (deleterious). BP4 requires multiple lines of computational evidence suggesting no impact on protein function, which is contradicted by the available scores.	revel bayesdel spliceai
BP5	Not met	No observation of this variant in a case where an alternate molecular basis for disease was identified. BP5 requires a variant found in a patient with a clear alternative genetic etiology.
BP6	Not met	No reputable source reports this variant as benign. ClinVar classification is VUS from a single submitter. BP6 requires a reputable source to have classified the variant as benign.	clinvar
BP7	N/A	This is a missense variant (c.3581G>T, p.Trp1194Leu), not a synonymous variant with no predicted splice impact. BP7 applies only to silent variants.

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