LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-07-21
Case ID: NM_000548.4_c.3715G_C_20260721_085707
Framework: ACMG/AMP 2015
Variant classification summary

NM_000548.4:c.3715G>C

TSC2  · NP_000539.2:p.(Glu1239Gln)  · NM_000548.4
GRCh37: chr16:2131700 G>C  ·  GRCh38: chr16:2081699 G>C
Gene: TSC2 Transcript: NM_000548.4
Final call
VUS
PM2 supporting PP3 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
TSC2
Transcript
NM_000548.4
Protein
NP_000539.2:p.(Glu1239Gln)
gnomAD AF
ClinVar
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
This variant is absent from all gnomAD population databases (v2.1, v4.1, and Canada), meeting PM2 at supporting strength.
2
Multiple in silico prediction tools (REVEL 0.577, BayesDel 0.312735) predict a deleterious effect for the p.Glu1239Gln substitution, meeting PP3 at supporting strength.
3
No variant-specific functional studies, case-control data, segregation data, de novo reports, or reputable source classifications were identified. ClinVar contains no exact match for this variant; the closest candidate is a different variant classified as uncertain significance.
4
The single associated publication (PMID:25394175) is a general ACMG/NSGC practice guideline on cancer genetics referral indications and does not mention this specific variant.
5
The only met criteria are PM2_supporting and PP3_supporting, which is insufficient to reach a likely pathogenic or pathogenic classification. This variant is classified as a variant of uncertain significance (VUS).
Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.
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 NM_000548.4:c.3715G>C is a missense substitution (p.Glu1239Gln) and does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per PMC6185798.
pvs1_generic_framework pvs1_variant_assessment
PS1 Not met No evidence that a different nucleotide change at the same codon resulting in the same amino acid substitution (p.Glu1239Gln) has been classified as pathogenic in ClinVar or the literature.
clinvar
PS2 Not met No de novo data are available for this variant. PubMed and ClinVar do not contain any report of de novo occurrence with confirmed parentage.
clinvar
PS3 Not met No variant-specific functional studies were identified. OncoKB reports unknown oncogenic effect; no COSMIC entries; no publications with variant-specific functional data.
oncokb
PS4 Not met No case-control or prevalence data demonstrating enrichment of this variant in affected individuals versus controls. The only associated publication (PMID:25394175) is a general cancer genetics referral guideline that does not mention this variant.
PMID:25394175
PS5 Not met No established pathogenic variant from a reputable source. The closest ClinVar candidate (NM_000548.5:c.3895G>C, p.Val1299Leu) is a different variant classified as uncertain significance by a single submitter (Ambry Genetics).
clinvar
PM1 Not met Residue 1239 does not fall within a statistically significant mutational hotspot per cancerhotspots.org, and no domain-level functional characterization data were identified for this specific region in the literature.
PM2 Met This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the PM2 threshold for absence in population databases (allele frequency < 0.1%).
gnomad_v2 gnomad_v4 gnomad_canada
PM5 N/A No same-residue pathogenic missense comparator variants identified in ClinVar; automated candidate harvesting could not confirm classic PM5 semantics.
pm5_candidates
PM6 Not met No de novo observation reported for this variant; no evidence of de novo occurrence without confirmation of paternity and maternity.
clinvar
PP1 Not met No co-segregation data are available for this variant. No family studies were identified.
PP2 Not met HCI prior score not available for TSC2; cannot assess whether TSC2 has a low rate of benign missense variation. Insufficient data to apply PP2.
PP3 Met Multiple in silico predictors suggest a deleterious effect: REVEL score 0.577 and BayesDel score 0.312735 both predict a damaging consequence for the p.Glu1239Gln substitution.
revel bayesdel
PP4 Not assessed No patient phenotype or clinical information is available in the case materials to assess whether the patient's phenotype is highly specific for TSC2-related disease.
PP5 Not met No reputable source has classified this variant as pathogenic. ClinVar has no exact match; the closest candidate is a different variant classified as VUS. The associated PMID (25394175) is a general cancer genetics referral guideline that does not mention this specific variant.
clinvar PMID:25394175
BA1 Not met This variant is absent from all gnomAD datasets (v2.1, v4.1, Canada) and does not meet the BA1 allele frequency threshold of >1%.
gnomad_v2 gnomad_v4 gnomad_canada
BS1 Not met This variant is absent from gnomAD and does not exceed the BS1 allele frequency threshold of >0.3%.
gnomad_v2 gnomad_v4 gnomad_canada
BS2 Not met No evidence that this variant has been observed in a healthy adult individual. gnomAD shows complete absence from population databases.
gnomad_v2 gnomad_v4
BS3 Not met No functional studies demonstrating a benign or neutral effect of the p.Glu1239Gln substitution were identified. No experimental characterization of this variant exists.
oncokb
BS4 Not met No segregation data are available to assess lack of co-segregation with disease. No family studies identified.
BP1 Not met TSC2 missense variants are an established cause of tuberous sclerosis complex (TSC); BP1 is only applicable when a gene primarily causes disease through truncating variants, which is not the case for TSC2.
pvs1_gene_context
BP2 Not met No data regarding observation of this variant in trans with a known pathogenic TSC2 variant. TSC2 disease is autosomal dominant; biallelic in trans observations are not expected in the typical disease context.
BP4 Not met Multiple in silico predictors suggest a damaging rather than benign effect: REVEL score 0.577 and BayesDel score 0.312735 both predict deleterious consequence. SpliceAI max delta 0.05 indicates no splicing impact but does not provide evidence of a benign effect for a missense variant.
revel bayesdel spliceai
BP5 Not met No alternative molecular basis for disease has been identified in this case. BP5 requires an established alternative cause, which has not been demonstrated.
BP6 Not met No reputable source has classified this variant as benign. ClinVar has no exact match for this variant; the closest candidate is a different variant classified as VUS.
clinvar
BP7 N/A NM_000548.4:c.3715G>C is a missense variant (p.Glu1239Gln), not a synonymous or intronic variant. BP7 does not apply.
spliceai
BP3 N/A Not an in-frame deletion or insertion in a non-repeat region; BP3 does not apply to missense substitutions.
PM3 N/A TSC2-related disease is autosomal dominant; PM3 (recessive disorder trans observation) is not applicable.
PM4 N/A Not a protein-length-altering variant (non-frameshift indel, stop-loss, or initiation codon change); PM4 does not apply to missense substitutions.
Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.