Starting

Initialising…

TSC2

Final classification

VUS

TSC2 c.97G>C · p.Gly33Arg

TSC2

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.

Gene

TSC2

Transcript

NM_000548.5

HGVS · transcript:coding

NM_000548.5:c.97G>C

Consequence

N/A

GRCh38

chr16:2048712 G>C

GRCh37

chr16:2098713 G>C

Basis 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, BP4 supporting benign; combination = 1 supporting, which maps to VUS because the evidence is conflicting. ▾

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, BP4 supporting benign; combination = 1 supporting, which maps to VUS because the evidence is conflicting.

Classification rationale

PM2 BP4 VUS

TSC2 c.97G>C

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.¹ 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.² 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.³ 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).⁴

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 revelbayesdelspliceai ↗

3 clinvar ↗oncokb ↗

4 generic_acmg_combination_rules

Gene diagram · NM_000548.5 · variants mapped to exon structure

TSC2 NM_000548.5

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 4802827)

ClinVar ↗

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 ↗

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.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

20301399 ↗ Tuberous Sclerosis Complex. CLINVAR

23519317 ↗ Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. CLINVAR

23788249 ↗ ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. CLINVAR

25356965 ↗ ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. CLINVAR

27854360 ↗ Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. CLINVAR

34012068 ↗ ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). CLINVAR

35802134 ↗ ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG). CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR