LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-03
Case ID: NM_000548.5_c.2476C_A_20260903_121348
Framework: ACMG/AMP 2015
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
VUS
PS2 strong BS2 supporting BS3 strong BS4 supporting
All criteria require review: For research and educational purposes only.
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
PS2 (Strong): confirmed de novo occurrence of c.2476C>A in sporadic TSC patient S19-01, with both parents tested.
2
BS3 (Strong): the exact p.L826M substitution preserved normal tuberin function in orthogonal assays, comparable to wild type and distinct from damaging comparators.
3
BS2 (Supporting): the variant was identified in a clinically unaffected father who transmitted it to both children.
4
BS4 (Supporting): non-segregation with TSC, as both children inherited L826M from their clinically unaffected father.
5
Overall: VUS, produced by the generic ACMG/AMP 2015 combination rule when strong pathogenic evidence conflicts with strong and supporting benign evidence.
Final determination: Under the generic ACMG/AMP fallback, conflicting pathogenic and benign evidence is classified as VUS.
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 missense substitution is not a null variant class (nonsense, frameshift, or canonical splice) that PVS1 requires.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not met Not met: no distinct nucleotide change producing p.Leu826Met was found; the exact c.2476C>A was reported instead.
PMID:15483652 PMID:9829910
PS2 Met Met (strong): confirmed de novo occurrence in sporadic TSC patient S19-01, with both parents tested negative.
PMID:9829910 PMID:25741868
PS3 Not met Not met: functional studies of the exact substitution showed preserved tuberin function, with binding, mTOR suppression, and rheb activity comparable to wild type.
PMID:15483652
PS4 Not assessed Not assessed: the variant appeared once among 20 sporadic TSC cases with no case-control analysis, so enrichment could not be established.
generic_acmg_combination_rules PMID:9829910 PMID:15483652 PMID:17120248
PM1 Not met Not met: no authoritative VCEP domain list applies, and the N-terminal TSC1-binding region is not established as a critical domain lacking benign variation.
PMID:22903760 PMID:21309039 PMID:15483652 gnomad_v4
PM2 Not met Not met: gnomAD v4.1 overall allele frequency is 0.13527%, above the <0.1% PM2 threshold.
gnomad_v4 gnomad_v2 gnomad_canada PMID:9829910 generic_acmg_combination_rules
PM3 N/A Not applicable: tuberous sclerosis is autosomal dominant, while PM3 applies to recessive disorders with a pathogenic variant in trans.
PMID:9829910
PM4 N/A Not applicable: as a missense substitution it causes no protein length change, which PM4 (in-frame or stop-loss) requires.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not met Not met: the same-residue p.Leu826Pro comparator (PMID:22903760) has no functional result and is not established as pathogenic.
PMID:22903760
PM6 N/A Not applicable: maternity and paternity were confirmed by parental testing, so the confirmed de novo criterion (PS2) applies instead.
PMID:9829910 PMID:25741868
PP1 Not met Not met: L826M was inherited from a clinically unaffected father by both children in Family B, inconsistent with disease segregation.
PMID:17120248 PMID:15483652 PMID:25741868
PP2 Not met Not met: evidence does not show pathogenic missense is common and benign missense rare in TSC2; the variant itself has benign functional evidence.
PMID:15483652 PMID:21309039 gnomad_v4
PP3 Not met Not met: REVEL score 0.638 is below the ClinGen-calibrated supporting PP3 threshold of 0.773.
revel generic_acmg_combination_rules
PP4 Not assessed Not assessed: no proband phenotype was available, so phenotype specificity for TSC2-related disease could not be evaluated.
generic_acmg_combination_rules PMID:9829910
PP5 Not assessed Not assessed: ClinVar has no expert-panel pathogenic or likely pathogenic assertion for this exact variant.
clinvar
BA1 Not met Not met: the highest observed allele frequency, 0.17372% (gnomAD v4.1 European non-Finnish), is far below the >1% BA1 threshold.
gnomad_v4 gnomad_v2 gnomad_canada generic_acmg_combination_rules
BS1 Not met Not met: the highest observed allele frequency, 0.17372% (gnomAD v4.1 European non-Finnish), is below the >0.3% BS1 threshold.
gnomad_v4 gnomad_v2 gnomad_canada generic_acmg_combination_rules
BS2 Met Met (supporting): the variant was found in a clinically unaffected father who transmitted it to both children. Flagged for human review: the reports lack detailed age, examination, and penetrance data for the carrier.
PMID:17120248 PMID:15483652 generic_acmg_combination_rules
BS3 Met Met (strong): the exact p.L826M substitution preserved tuberin function, with binding, mTOR suppression, and rheb GAP activity comparable to wild type.
PMID:15483652 PMID:17120248
BS4 Met Met (supporting): non-segregation with TSC, as both children in Family B inherited L826M from their clinically unaffected father.
PMID:17120248 PMID:15483652 PMID:25741868
BP1 Not met Not met: TSC2 has a substantial, experimentally documented missense disease mechanism, so it is not a primarily truncating gene for BP1.
PMID:15483652 PMID:22903760 PMID:21309039
BP2 Not assessed Not assessed: the record does not show L826M in trans with a known pathogenic variant, so the required phase is unestablished.
PMID:17120248
BP3 N/A Not applicable: as a missense substitution it does not alter protein length within a repetitive region, BP3's prerequisite.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Not met Not met: REVEL score 0.638 is above the ClinGen-calibrated supporting BP4 threshold of 0.290.
revel generic_acmg_combination_rules
BP5 Not assessed Not assessed: no evidence of an alternate molecular diagnosis fully explaining the phenotype was available.
generic_acmg_combination_rules
BP6 Not assessed Not assessed: ClinVar has no expert-panel benign or likely benign assertion for this exact variant.
clinvar
BP7 N/A Not applicable: BP7 applies to synonymous variants, and this missense substitution alters the encoded protein.
generic_acmg_combination_rules
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