Variant classification summary

NM_000548.5:c.2476C>A

TSC2 · NP_000539.2:p.(Leu826Met) · NM_000548.5

GRCh37: chr16:2124321 C>A · GRCh38: chr16:2074320 C>A

Gene: TSC2 Transcript: NM_000548.5

Final call

Likely Benign

BS2 supporting BS3 moderate BS4 supporting

Variant details

Gene

TSC2

Transcript

NM_000548.5

Protein

NP_000539.2:p.(Leu826Met)

gnomAD AF

0.0013527034851642773 (v4.1)

ClinVar

Likely benign

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BS2 (Supporting): variant reported as a polymorphism inherited from an unaffected father with no effect on TSC2 protein function.

2

BS3 (Moderate): direct functional assays showed p.Leu826Met behaves like wild-type tuberin across multiple readouts, with no damaging effect.

3

BS4 (Supporting): the variant non-segregates with disease, inherited by both children from an unaffected father.

4

Overall: Likely Benign under generic ACMG/AMP 2015 combination rules — BS2, BS3, and BS4 met, no pathogenic criteria applied.

Final determination: Generic ACMG/AMP 2015: 2+ supporting-strength benign criteria (BS2, BS4) with no conflicting pathogenic evidence → Likely Benign; BS3 corroborates but full Benign (2 strong BS or BA1) not reached.

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	Not applicable: this is a missense substitution, so no null-variant mechanism (nonsense-mediated decay, truncation, or splice disruption) is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no differently-coded variant producing the same p.Leu826Met substitution with an established pathogenic classification was identified.	pm5_candidates
PS2	Not assessed	Not assessed: no evidence that the variant arose de novo in an affected proband with confirmed maternity and paternity was available.	PMID:15798777
PS3	Not met	Not met: direct functional assays showed p.Leu826Met behaved like wild-type tuberin, with no damaging effect across any readout.
PS4	Not assessed	Not assessed: no case-control or enrichment evidence for this variant among individuals with tuberous sclerosis was available.	PMID:15483652 PMID:17120248
PM1	Not met	Not met: residue 826 lies in a broad ~900-residue N-terminal region rather than a small curated hotspot, and direct functional data show the substitution is nonpathogenic.	PMID:21309039 PMID:15483652 PMID:17120248 gnomad_v2
PM2	Not met	Not met: gnomAD v4.1 overall allele frequency is 0.135%, above the <0.1% PM2 rare-variant cutoff.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	N/A	Not applicable: tuberous sclerosis is autosomal dominant, so the recessive in-trans requirement does not apply.	PMID:25741868
PM4	N/A	Not applicable: this missense substitution causes no protein length change, so the in-frame indel or stop-loss criterion has nothing to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no same-residue missense change with an established pathogenic classification was identified; the only alternate, p.Leu826Pro, comes from a somatic functional panel.	pm5_candidates PMID:22903760
PM6	Not assessed	Not assessed: no evidence of presumed de novo occurrence without confirmed parentage was available.	PMID:15798777
PP1	Not assessed	Not assessed: no supportive segregation series exists; the variant was inherited from an unaffected father, which is non-segregating.	PMID:17120248
PP2	Not assessed	Not assessed: no TSC2 missense constraint metric, such as a gnomAD missense Z-score, was available to evaluate this criterion.
PP3	Not met	Not met: REVEL score 0.638 is below the ≥0.644 PP3 supporting threshold, in the inconclusive zone.	revel spliceai bayesdel
PP4	Not assessed	Not assessed: no phenotype-specificity information for the tested individual was provided.
PP5	Not met	Not met: ClinVar has no expert-panel Pathogenic or Likely Pathogenic assertion for this exact variant.	clinvar
BA1	Not met	Not met: the highest gnomAD v4.1 subpopulation frequency is 0.17%, far below the >1% BA1 threshold.	gnomad_v4 gnomad_v2 gnomad_canada
BS1	Not met	Not met: the highest gnomAD v4.1 subpopulation frequency is 0.17%, below the >0.3% BS1 threshold.	gnomad_v4 gnomad_v2 gnomad_canada
BS2	Met	Met (Supporting): the variant was reported as a polymorphism inherited from an unaffected father, with no effect on TSC2 protein function.	PMID:17120248 PMID:15483652
BS3	Met	Met (Moderate): direct functional assays showed p.Leu826Met behaved like wild-type tuberin across multiple concordant readouts, with no damaging effect.	PMID:15483652 PMID:17120248 PMID:21309039
BS4	Met	Met (Supporting): both children inherited the variant from their unaffected father, demonstrating non-segregation with disease.	PMID:17120248
BP1	Not met	Not met: missense variants are an established cause of TSC2 disease, so the truncation-only premise does not hold.	PMID:17120248 PMID:21309039 PMID:15798777
BP2	Not assessed	Not assessed: no pathogenic variant in the same individuals was documented, so phase with such a variant could not be established.	PMID:17120248 PMID:15483652 PMID:25741868
BP3	N/A	Not applicable: this missense substitution does not alter protein length, so the in-frame repeat-region criterion does not apply.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL score 0.638 is above the ≤0.290 BP4 supporting threshold, in the inconclusive zone.	revel spliceai bayesdel
BP5	Not assessed	Not assessed: no data linking the tested individual to an alternate phenotype-causing molecular diagnosis were available.
BP6	Not met	Not met: ClinVar has no expert-panel Benign or Likely Benign assertion for this exact variant.	clinvar
BP7	N/A	Not applicable: the variant is missense, not synonymous, so the silent-variant premise does not hold.	generic_acmg_combination_rules

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