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LYFE SCIENCES
Project: HERA
NM_000548.5:c.97G>C
p.Gly33Arg  ·  TSC2
ACMG/AMP
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Classification rationale
1

NM_000548.5:c.97G>C (p.Gly33Arg) in TSC2 is a missense variant absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, supporting PM2 at supporting strength.

gnomad_v2 ↗ gnomad_v4 ↗ gnomad_canada ↗
2

Multiple lines of computational evidence (REVEL 0.212, BayesDel 0.118, SpliceAI max delta 0.00) suggest no deleterious impact on the gene product, supporting BP4 at supporting benign strength.

spliceai ↗
3

No functional studies, case reports, segregation data, de novo observations, or ClinVar pathogenic classifications exist for this specific variant. The sole ClinVar submission classifies it as Uncertain Significance.

clinvar ↗ oncokb ↗
4

Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) yields a final classification of Variant of Uncertain Significance (VUS).

Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
—
Research and evidence
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 4802827)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.212. BayesDel score = 0.118026.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueG33
Hotspots ↗