NM_000548.4:c.4751T>C

TSC2 · NP_000539.2:p.(Leu1584Pro) · NM_000548.4

GRCh37: chr16:2136282 T>C · GRCh38: chr16:2086281 T>C

Gene: TSC2 Transcript: NM_000548.4

Final call

VUS

PM1 supporting PM2 supporting PP3 supporting

Variant details

Gene

TSC2

Transcript

NM_000548.4

Protein

NP_000539.2:p.(Leu1584Pro)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000548.4:c.4751T>C (p.Leu1584Pro) is a missense variant in exon 37 of TSC2.

The variant is located within the Rap-GAP domain (residues 1531-1758), a critical functional domain of TSC2 responsible for GTPase-activating protein activity essential for mTORC1 inhibition. Leucine 1584 resides within an alpha-helical segment (1584-1586), and substitution to proline is predicted to disrupt helical structure (PM1_supporting).

The variant is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (PM2_supporting).

Multiple in silico tools predict a deleterious effect: REVEL score 0.989 is strongly damaging and BayesDel score 0.569902 supports a deleterious prediction (PP3_supporting).

SpliceAI predicts no splicing impact (max delta score 0.00), indicating the predicted effect is at the protein level rather than through altered splicing.

No variant-specific functional studies were confirmed. PMID:22903760 tested 78 TSC2 variants for functional effects on TORC1 inhibition, but L1584P could not be verified among those tested from available evidence.

ClinVar reports this variant as Uncertain significance (1 star, single submitter from Labcorp/Invitae), which does not contribute to PP5 or BP6.

No de novo, cosegregation, case-control, or detailed phenotype data are available to support PS2, PS4, PP1, or PP4.

With PM1_supporting, PM2_supporting, and PP3_supporting as the only criteria met (3 supporting-level pathogenic criteria), the variant does not reach the threshold for Likely Pathogenic classification under ACMG/AMP 2015 rules. The variant is classified as a Variant of Uncertain Significance (VUS) trending toward pathogenic.

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	NM_000548.4:c.4751T>C (p.Leu1584Pro) is a missense variant, not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). Does not meet PVS1 decision tree eligibility under PMC6185798 generic framework.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not assessed	No evidence of a different nucleotide change at c.4751 producing the same amino acid change (p.Leu1584Pro) was identified.
PS2	Not met	No de novo occurrence data available for this variant.
PS3	Not assessed	No variant-specific functional data confirmed for p.Leu1584Pro. PMID:22903760 (Hoogeveen-Westerveld 2013) tested 78 TSC2 variants for TSC1-TSC2-mediated TORC1 inhibition, but the presence of L1584P among the tested variants could not be verified from available data (full text unavailable, OncoKB reports no variant-specific reviewed functional evidence).	PMID:22903760 oncokb
PS4	Not met	Variant reported in ClinVar (VCV001052460) as Uncertain significance by a single clinical laboratory (Invitae); no case-control data or statistically significant enrichment in affected individuals available.	clinvar
PS5	N/A	Skipped per case instructions.
PM1	Met	The variant p.Leu1584Pro is located within the Rap-GAP domain (residues 1531-1758) of TSC2, a well-characterized critical functional domain responsible for GTPase-activating protein activity essential for mTORC1 inhibition. UniProt annotates multiple nearby residues as functionally characterized: positions 1643 and 1681 abolish GAP activity, and mutagenesis at 1594 decreases GAP activity. Additionally, leucine to proline substitution at position 1584, which resides within an alpha-helical region (residues 1584-1586), is predicted to disrupt local secondary structure.
PM2	Met	Variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases, consistent with a rare variant. Allele frequency <0.1% threshold for PM2 is met (absent).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator variants with a different amino acid change identified as pathogenic. Automated PM5 candidate harvest found 0 candidates at residue 1584.	pm5_candidates
PM6	Not met	No de novo occurrence data available for this variant.
PP1	Not met	No cosegregation data available for this variant.
PP2	Not assessed	HCI prior score not available for TSC2 (gene_not_supported). TSC2 is a known tumor suppressor with disease-causing missense variants, but without gene-specific missense constraint metrics (Z-score, missense depletion data), PP2 cannot be reliably applied.
PP3	Met	Multiple in silico tools predict a deleterious effect: REVEL score 0.989 (highly damaging), BayesDel score 0.569902 (deleterious). Additionally, leucine to proline substitution within an alpha-helical segment (residues 1584-1586) of the Rap-GAP domain is mechanistically consistent with structural disruption. SpliceAI predicts no splicing impact (max delta 0.00), indicating the predicted effect is at the protein level.	revel bayesdel spliceai
PP4	Not met	No detailed phenotype or family history data available. ClinVar lists the associated condition as Tuberous sclerosis 2, but the single submission provides no patient-specific clinical details.	clinvar
PP5	Not met	ClinVar classification is Uncertain significance with 1-star review status (criteria provided, single submitter). PP5 requires a reputable source reporting the variant as pathogenic; 1-star VUS does not meet the 3-star expert panel threshold for PP5 application.	clinvar
BA1	Not met	Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. Does not meet BA1 threshold of allele frequency >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. Does not meet BS1 threshold of allele frequency >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No evidence of observation in healthy adults with expected full penetrance at an early age.
BS3	Not met	No functional studies demonstrating no damaging effect on protein function or splicing for this variant.
BS4	Not met	No cosegregation data available; cannot evaluate lack of segregation with disease.
BP1	Not met	TSC2 missense variants are established causes of tuberous sclerosis complex. BP1 applies only to genes where solely truncating variants cause disease, which is not the case for TSC2.	clinvar
BP2	Not met	No evidence of observation in trans with a known pathogenic dominant variant in TSC2.
BP4	Not met	REVEL score 0.989 and BayesDel score 0.569902 predict a damaging effect, contradicting BP4 application. Multiple in silico tools support a deleterious prediction.	revel bayesdel
BP5	Not met	No evidence of an alternate molecular basis for disease in the affected individual(s).
BP6	Not met	ClinVar classification is Uncertain significance (1 star, single submitter). No reputable source classifies this variant as benign or likely benign.	clinvar
BP7	Not met	NM_000548.4:c.4751T>C is a missense variant (p.Leu1584Pro), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.	spliceai
BP3	N/A	BP3 applies to in-frame indels; this variant is a missense substitution.
PM3	N/A	PM3 applies to recessive disorders; TSC2-associated tuberous sclerosis complex is autosomal dominant.
PM4	N/A	PM4 applies to non-repeat non-truncating variants (in-frame indels, stop-loss); this is a missense substitution.

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