LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-06
Case ID: NM_000548.5_c.5024C_T_20261106_111729
Framework: ACMG/AMP 2015
Variant classification summary

NM_000548.5:c.5024C>T

TSC2  · NP_000539.2:p.(Pro1675Leu)  · NM_000548.5
GRCh37: chr16:2137898 C>T  ·  GRCh38: chr16:2087897 C>T
Gene: TSC2 Transcript: NM_000548.5
Final call
Pathogenic
PS1 strong PS3 moderate PM2 supporting PM6 moderate PP3 strong
All criteria require review: For research and educational purposes only.
Variant details
Gene
TSC2
Transcript
NM_000548.5
Protein
NP_000539.2:p.(Pro1675Leu)
gnomAD AF
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PS1 strong supports the exact recurrent pathogenic Pro1675Leu substitution.
2
Pathogenic: PS3 moderate supports impaired TSC2-TORC1 function in a replicated controlled assay.
3
Pathogenic: PM2 supporting reflects absence from all reported gnomAD datasets.
4
Pathogenic: PM6 moderate reflects a reported de novo occurrence without documented parentage confirmation.
5
Pathogenic: PP3 strong reflects REVEL 0.965 above the generic strong threshold and counts toward the supporting tier.
Final determination: Under generic ACMG/AMP 2015 rules, one Strong pathogenic criterion plus two Moderate and at least two Supporting pathogenic criteria supports Pathogenic; the Strong PP3 criterion also satisfies the lower Supporting tier.
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: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Met Met: the exact P1675Leu substitution was previously reported as pathogenic and recurrent in at least two unrelated patients.
PMID:12111193 PMID:12205112
PS2 Not met Not met: de novo status was reported after parental testing, but confirmation of both maternity and paternity is not documented.
PMID:10570911
PS3 Met Met moderate: four-replicate HEK293T assay showed reduced TSC2 signal and increased T389-S6K signaling versus wild type, supporting impaired TORC1 inhibition.
PMID:22903760 PMID:12205112
PS4 Not assessed Not assessed: affected cases were reported, but no control frequency, OR/RR, or confidence interval was available for comparison with the >5.0 PS4 threshold.
PMID:10570911 PMID:12111193 PMID:12136241 PMID:12205112 PMID:22903760 gnomad_v2 gnomad_v4
PM1 Not assessed Not assessed: Pro1675 lies in the GAP-related domain, but domain-wide absence of benign variation is not established by the available evidence.
PMID:12205112 hotspots
PM2 Met Met at supporting strength: the variant is absent from all reported gnomAD datasets, giving observed frequency 0 versus the PM2 threshold of <=0.0001.
gnomad_v2 gnomad_v4
PM3 N/A Not applicable: TSC2-related disease is autosomal dominant, whereas PM3 applies only to recessive disorders with a pathogenic variant in trans.
PMID:22903760 PMID:10570911
PM4 N/A Not applicable: PM4 requires a protein-length change, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not assessed Not assessed: no confirmed pathogenic different-missense comparator at residue 1675 is documented in the available evidence.
PM6 Met Met: patient P28's matched variant was reported de novo after parental sample testing without documented maternity and paternity confirmation.
PMID:10570911
PP1 Not assessed Not assessed: no affected relatives or informative family meioses are reported for evaluating co-segregation.
PMID:10570911 PMID:12136241
PP2 Not assessed Not assessed: neither a low benign-missense rate nor a common missense disease mechanism is established for TSC2 here.
PP3 Met Met strong: missense REVEL 0.965 meets the PP3 strong threshold of >=0.932.
revel
PP4 Not assessed Not assessed: the evaluated patient's phenotype and family history were not provided, so specificity for a single genetic etiology cannot be judged.
PP5 Not met Not met: ClinVar has zero expert-panel submissions, and the exact-variant evidence is available for independent evaluation rather than qualifying as an expert-panel PP5 assertion.
clinvar
BA1 Not met Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than reaching the generic BA1 allele-frequency threshold of >=0.05.
gnomad_v2 gnomad_v4
BS1 Not met Not met: the variant is absent from gnomAD v2.1 and v4.1, with no grpmax FAF approaching the generic BS1 default threshold of 0.01.
gnomad_v2 gnomad_v4
BS2 Not met Not met: no healthy adult carrier or homozygous observation is reported, and absence from gnomAD cannot establish the BS2 observation requirement.
gnomad_v2 gnomad_v4
BS3 Not met Not met: the controlled assay showed reduced TSC2 signal and increased T389-S6K signaling, while a wild-type-like G1 result did not establish normal overall function.
PMID:22903760 PMID:12205112
BS4 Not assessed Not assessed: no affected relatives with negative variant testing are reported to demonstrate lack of segregation.
PMID:10570911 PMID:12136241
BP1 Not met Not met: established pathogenic and functionally studied TSC2 missense variation contradicts a primarily truncating-only disease mechanism.
PMID:12111193 PMID:22903760
BP2 Not assessed Not assessed: no second pathogenic variant with documented cis/trans phase is reported, so neither BP2 configuration can be established.
PMID:12136241 PMID:10570911 PMID:12111193
BP3 N/A Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Not met Not met: missense REVEL 0.965 is above the BP4 supporting threshold of <=0.29.
revel
BP5 Not assessed Not assessed: no specific case was documented with an alternate molecular basis for the disease in addition to this variant.
BP6 Not met Not met: no exact-variant reputable benign or likely-benign assertion was found, while ClinVar reports Pathogenic and zero expert-panel submissions.
clinvar
BP7 N/A Not applicable: BP7 requires a synonymous variant, and this is a missense variant.
generic_acmg_combination_rules
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