Variant classification summary

NM_000548.4:c.3796_3797del

TSC2 · NP_000539.2:p.(Leu1266AlafsTer55) · NM_000548.4

GRCh37: chr16:2131778 CCT>C · GRCh38: chr16:2081777 CCT>C

Gene: TSC2 Transcript: NM_000548.4

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

TSC2

Transcript

NM_000548.4

Protein

NP_000539.2:p.(Leu1266AlafsTer55)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): 2-bp deletion causes frameshift p.(Leu1266AlafsTer55), a null variant predicted to trigger nonsense-mediated decay in TSC2, where loss of function is an established disease mechanism.

2

PM2 (Supporting): variant is absent from gnomAD v2.1/v4.1 exomes and gnomAD-Canada genomes (allele frequency 0, below the 0.1% threshold).

3

Overall: Likely Pathogenic, per the ACMG/AMP combination rule PVS1 + 1 supporting criterion (posterior probability 0.988).

Final determination: Under the generic ACMG/AMP 2015 fallback (no TSC2 VCEP/CSPEC exists), the combination of 1 very strong criterion (PVS1) plus 1 supporting criterion (PM2, downgraded to supporting per ClinGen SVI) satisfies the (1 PVS1) + (1 PP) rule -> Likely Pathogenic (ClinGen SVI 2020 PM2-downgrade addendum: PVS1 + 1 supporting criterion = LP, Post_P 0.988).

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	Met	Met at very strong: 2-bp deletion causes frameshift p.(Leu1266AlafsTer55), a null variant predicted to trigger nonsense-mediated decay in TSC2, a gene with an established loss-of-function disease mechanism.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment clinvar PMID:10205261 PMID:17304050 gnomad_v2 gnomad_v4 spliceai
PS1	N/A	Not applicable: as a frameshift, no altered amino acid exists to compare against an established pathogenic missense at the same position.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no de novo occurrence data exist for this variant; parental testing results for the proband are missing.
PS3	Not met	Not met: no well-established functional study of this exact variant exists; the OncoKB loss-of-function annotation is curated inference, not an experimental assay.	oncokb PMID:10205261 PMID:14561707 PMID:14729330 PMID:24529379 PMID:25724664 PMID:25741868 generic_acmg_combination_rules
PS4	Not assessed	Not assessed: no case-level data show this exact variant enriched in affected individuals; the two large TSC cohort studies do not report it.	PMID:10205261 PMID:17304050 clinvar gnomad_v2 gnomad_v4
PM1	N/A	Not applicable: as a frameshift, no altered residue exists to evaluate for mutational hotspot or critical-domain membership.	generic_acmg_combination_rules
PM2	Met	Met at supporting: variant is absent from gnomAD v2.1 and v4.1 exomes and gnomAD-Canada genomes (allele frequency 0, below the 0.1% threshold).	gnomad_v2 gnomad_v4 gnomad_canada clinvar PMID:25741868 PMID:17304050
PM3	N/A	Not applicable: TSC2-related tuberous sclerosis is autosomal dominant, so the in-trans requirement for recessive disorders cannot apply.	PMID:25741868 PMID:17304050 PMID:10205261
PM4	N/A	Not applicable: as a frameshift that does not change protein length, there is no in-frame indel or stop-loss variant to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: as a frameshift, no missense change exists at this residue to compare against a known pathogenic missense.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no parental testing observation, even without parentage confirmation, is reported for this variant.
PP1	Not assessed	Not assessed: no co-segregation data exist; no family carrying this exact variant is reported.
PP2	N/A	Not applicable: as a frameshift, no missense change is present, so the gene's missense-constraint properties are irrelevant.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.01 is far below the 0.2 splice-impact threshold, and missense predictors do not apply to a deletion.	spliceai PMID:25741868
PP4	Not assessed	Not assessed: no proband phenotype or family history is documented to establish a highly specific TSC presentation.	clinvar
PP5	Not met	Not met: no ClinVar expert-panel (3-star) classification exists for this variant; laboratory P/LP labels do not qualify.	clinvar
BA1	Not met	Not met: allele frequency is 0 in gnomAD v2.1, v4.1, and gnomAD-Canada, far below the >1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
BS1	Not met	Not met: allele frequency 0 is not greater than the >0.3% threshold expected for this early-onset dominant disorder.	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868 PMID:17304050
BS2	Not met	Not met: no healthy-adult or homozygous observations exist; the variant is absent from all queried population datasets.	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868 PMID:17304050
BS3	Not met	Not met: no functional study shows normal protein function; SpliceAI's low splice score (0.01) does not address the frameshift's protein impact.	spliceai PMID:25741868 generic_acmg_combination_rules
BS4	Not assessed	Not assessed: no segregation study exists showing the variant in unaffected carriers or absent in affected relatives.
BP1	N/A	Not applicable: as a frameshift, no missense change exists, so the truncating-variant mechanism is irrelevant to this criterion.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no phased observations exist; no proband genotype or cis/trans testing is available for this variant.	PMID:25741868 clinvar PMID:17304050
BP3	N/A	Not applicable: as a frameshift, there is no in-frame change in a repetitive region without known function to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: SpliceAI's low score (0.01) addresses splicing only and cannot offset the frameshift's unambiguous protein-truncating impact.	spliceai PMID:25741868
BP5	Not assessed	Not assessed: no proband workup data exist to show an alternate molecular basis of disease.
BP6	Not met	Not met: ClinVar has no benign or likely-benign submissions and no expert-panel classification for this variant.	clinvar
BP7	N/A	Not applicable: the variant is a frameshift, not a synonymous change, so the silent-variant premise does not hold.	generic_acmg_combination_rules

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