Variant classification summary

NM_000548.5:c.3834G>A

TSC2 · NP_000539.2:p.(Leu1278=) · NM_000548.5

GRCh37: chr16:2132456 G>A · GRCh38: chr16:2082455 G>A

Gene: TSC2 Transcript: NM_000548.5

Final call

VUS

PM2 supporting BP7 supporting

Variant details

Gene

TSC2

Transcript

NM_000548.5

Protein

NP_000539.2:p.(Leu1278=)

gnomAD AF

6.201588847062617e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: the gnomAD v4.1 allele frequency is 6.20159e-07, below the generic supporting threshold of 0.0001.

2

BP7 supporting: the synonymous variant has a SpliceAI maximum delta of 0.112, below the 0.2 threshold for significant predicted splice impact.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting pathogenic criterion and one supporting benign criterion do not meet any defined pathogenic, likely pathogenic, likely benign, or benign combination, so the result is 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	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_000548.5:c.3834G>A in TSC2 is a synonymous (silent) substitution predicted to produce NP_000539.2:p.(Leu1278=). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_000548.5:c.3834G>A in TSC2 is a synonymous (silent) substitution predicted to produce NP_000539.2:p.(Leu1278=). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: parental genotypes and confirmed maternity/paternity are not documented for this variant.
PS3	Not assessed	Not assessed: no variant-specific validated functional assay or disease-relevant abnormality is available for c.3834G>A (p.Leu1278=).
PS4	Not assessed	Not assessed: no variant-specific affected-versus-control counts or enrichment statistic were available for PS4.	clinvar PMID:20301399 PMID:23788249 PMID:25356965 PMID:27854360 PMID:34012068
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_000548.5:c.3834G>A in TSC2 is a synonymous (silent) substitution predicted to produce NP_000539.2:p.(Leu1278=). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM2	Met	Met at supporting strength: gnomAD v4.1 allele frequency is 6.20159e-07, below the generic PM2 threshold of 0.0001.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
PM3	N/A	Not applicable: TSC2-associated tuberous sclerosis complex is autosomal dominant, so recessive biallelic-in-trans PM3 evidence does not apply.
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000548.5:c.3834G>A in TSC2 is a synonymous (silent) substitution predicted to produce NP_000539.2:p.(Leu1278=). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_000548.5:c.3834G>A in TSC2 is a synonymous (silent) substitution predicted to produce NP_000539.2:p.(Leu1278=). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: presumed de novo status, parental testing, and a consistent proband phenotype are not documented.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or genotype–phenotype segregation data are available.
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_000548.5:c.3834G>A in TSC2 is a synonymous (silent) substitution predicted to produce NP_000539.2:p.(Leu1278=). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PP3	N/A	Not applicable: c.3834G>A is synonymous (p.Leu1278=), outside PP3's missense or intronic/splice-region scope.
PP4	Not assessed	Not assessed: no patient phenotype or family history was provided to evaluate specificity for tuberous sclerosis complex.	clinvar PMID:27854360
PP5	Not met	Not met: the exact ClinVar variant has zero expert-panel submissions and no Pathogenic or Likely pathogenic expert-panel classification.	clinvar
BA1	Not met	Not met: the highest observed allele frequency is 1.77016e-05, far below the generic BA1 threshold of 0.05.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1	Not met	Not met: the highest observed allele frequency is 1.77016e-05, below the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD reports 0 homozygotes and only rare heterozygotes, without phenotype-confirmed healthy individuals establishing BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific validated assay demonstrates normal function for c.3834G>A (p.Leu1278=).
BS4	Not assessed	Not assessed: no tested unaffected relatives or reliable non-segregation observations are documented.
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_000548.5:c.3834G>A in TSC2 is a synonymous (silent) substitution predicted to produce NP_000539.2:p.(Leu1278=). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no second pathogenic variant or cis/trans phase result is documented for NM_000548.5:c.3834G>A.	clinvar
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000548.5:c.3834G>A in TSC2 is a synonymous (silent) substitution predicted to produce NP_000539.2:p.(Leu1278=). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: c.3834G>A is synonymous (p.Leu1278=), outside BP4's missense or intronic/splice-region scope.
BP5	Not assessed	Not assessed: no patient phenotype or alternate pathogenic molecular diagnosis was provided to establish another cause.	clinvar
BP6	Not met	Not met: the exact ClinVar Likely benign assertion is from a single laboratory, while zero expert-panel submissions are recorded.	clinvar
BP7	Met	Met, supporting: synonymous c.3834G>A has SpliceAI max delta 0.112, below the 0.2 significant-impact cutoff.	spliceai

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