This variant is absent from all gnomAD population databases (v2.1, v4.1, and Canada), meeting PM2 at supporting strength.1 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.2 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.3 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.4 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).5
TSC2
Final classification
VUS
TSC2 c.3715G>C · p.Glu1239Gln
TSC2
This variant is absent from all gnomAD population databases (v2.1, v4.1, and Canada), meeting PM2 at supporting strength.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP3 supporting; combination = 2 supporting, which maps to VUS.
Classification rationale
PM2PP3
VUS
TSC2 c.3715G>C
PM2 + PP3
→
VUS
2
revelbayesdel
5
generic_acmg_combination_rules
Gene diagram
· NM_000548.4 · variants mapped to exon structure
TSC2
NM_000548.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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%).
Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (exomes).Absent from gnomAD-Canada v1.0.
✓
PP3
supporting
Pathogenic
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 score: 0.577 (damaging).BayesDel score: 0.312735 (damaging range).
Assessed · not applied
Pathogenic
PS1
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.
PS2
No de novo data are available for this variant.
PS3
No variant-specific functional studies were identified.
PS4
No case-control or prevalence data demonstrating enrichment of this variant in affected individuals versus controls.
PM1
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.
PM6
No de novo observation reported for this variant; no evidence of de novo occurrence without confirmation of paternity and maternity.
PP1
No co-segregation data are available for this variant.
PP2
HCI prior score not available for TSC2; cannot assess whether TSC2 has a low rate of benign missense variation.
PP4
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
No reputable source has classified this variant as pathogenic.
Benign
BA1
This variant is absent from all gnomAD datasets (v2.1, v4.1, Canada) and does not meet the BA1 allele frequency threshold of >1%.
BS1
This variant is absent from gnomAD and does not exceed the BS1 allele frequency threshold of >0.3%.
BS2
No evidence that this variant has been observed in a healthy adult individual.
BS3
No functional studies demonstrating a benign or neutral effect of the p.Glu1239Gln substitution were identified.
BS4
No segregation data are available to assess lack of co-segregation with disease.
BP1
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.
BP2
No data regarding observation of this variant in trans with a known pathogenic TSC2 variant.
BP4
Multiple in silico predictors suggest a damaging rather than benign effect: REVEL score 0.577 and BayesDel score 0.312735 both predict deleterious consequence.
BP5
No alternative molecular basis for disease has been identified in this case.
BP6
No reputable source has classified this variant as benign.
N/A · 6
PVS1 · PM3 · PM4 · PM5 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.577. BayesDel score = 0.312735.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TSC2, a GTPase-activating protein, is altered by mutation in various cancers, including endometrial and colorectal cancer.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 1 PMID not cited in assessment
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR