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TSC2c.97G>CUncertain significance
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Variant interpretation report

TSC2 c.97G>C, p.(Gly33Arg)

NM_000548.5:c.97G>C NP_000539.2:p.(Gly33Arg) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About TSC2

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

NM_000548.5:c.97G>C is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). For non-VCEP assessment under generic ACMG/AMP, PM2 is applied when allele frequency is below 0.1% in all population databases. Complete absence across all queried populations supports PM2 at supporting strength.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.212 (below 0.5 pathogenic threshold). BayesDel score is 0.118 (low). SpliceAI predicts no splicing alteration (max delta score = 0.00). All three in silico predictors are concordant in not supporting a deleterious effect.

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 Uncertain significance.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 18 not met · 2 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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.

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.

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).

Met · 2

PM2 SupportingNM_000548.5:c.97G>C is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). For non-VCEP assessment under generic ACMG/AMP, PM2 is applied when allele frequency is below 0.1% in all population databases. Complete absence across all queried populations supports PM2 at supporting strength. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles)
  • gnomAD v4.1 (0 alleles)
  • gnomAD-Canada v1.0 (0 alleles).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.212 (below 0.5 pathogenic threshold). BayesDel score is 0.118 (low). SpliceAI predicts no splicing alteration (max delta score = 0.00). All three in silico predictors are concordant in not supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.212. BayesDel: 0.118. SpliceAI: max delta 0.00. All predictors concordant for no damaging effect.
Sources
revelbayesdelspliceai ↗

Not met · 18 · evaluated, threshold not reached

PS2 No de novo occurrence of NM_000548.5:c.97G>C has been reported. Targeted exploratory search for de novo evidence returned no relevant publications or database entries. Details ▾Hide ▴
Evidence considered
  • No de novo observation found in literature
  • DECIPHER
  • or ClinVar.
Still missing
  • No de novo data available for this variant.
PS3 No well-established in vitro or in vivo functional studies have tested NM_000548.5:c.97G>C (p.Gly33Arg). Gene-level functional assay frameworks exist for TSC2 (PMID:15798776, PMID:11274443) but do not include this specific variant. OncoKB classification is Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. Details ▾Hide ▴
Evidence considered
  • Gene-level TSC2 functional assays exist but none include c.97G>C. OncoKB: Unknown Oncogenic Effect
  • not reviewed.
Still missing
  • No functional data for this specific variant.
Sources
oncokb ↗
PS4 No case-control or cohort study has demonstrated statistically significant enrichment of NM_000548.5:c.97G>C in affected individuals versus controls. The variant is absent from gnomAD (v2.1, v4.1, Canada), precluding any odds-ratio calculation. Only a single ClinVar submission (Labcorp/Invitae, VUS) exists, which does not satisfy PS4 prevalence requirements. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1/v4.1/Canada. Single ClinVar VUS submission with no case counts.
Still missing
  • No case counts or case-control data available.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗clinvar ↗
PM1 Residue Gly33 is located in exon 2, in the N-terminal region of TSC2, distant from the critical GAP domain (residues ~1517-1766). Cancer Hotspots does not identify codon 33 as a statistically significant mutational hotspot. No evidence that this residue lies within a well-established critical functional domain devoid of benign variation. Details ▾Hide ▴
Evidence considered
  • Gly33 is not in the TSC2 GAP domain. Cancer Hotspots: residue G33 is not a significant hotspot (q-value unavailable
  • residue row not visible).
Still missing
  • No domain-level constraint data specific to TSC2 N-terminal region.
Sources
hotspots ↗
PM6 No de novo observation of NM_000548.5:c.97G>C has been reported, with or without confirmation of paternity/maternity. Targeted exploratory search returned no evidence. Details ▾Hide ▴
Evidence considered
  • No de novo observation found.
Still missing
  • No de novo data available.
PP1 No segregation data are available for NM_000548.5:c.97G>C. No family studies or LOVD entries with cosegregation information were identified. Details ▾Hide ▴
Evidence considered
  • No segregation data found in literature or databases.
Still missing
  • No family or segregation data available.
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.212 (well below the 0.5 threshold). BayesDel score is 0.118 (low, not supporting pathogenicity). SpliceAI predicts no splice impact (max delta score = 0.00). The variant does not lie in a known functional domain or hotspot. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.212. BayesDel: 0.118. SpliceAI max delta: 0.00. No in silico predictor supports a damaging effect.
Sources
revelbayesdelspliceai ↗
PP4 No specific phenotypic data or clinical information about the proband are available. The single ClinVar submitter classified this variant as VUS. No expert panel or consensus classification exists. Details ▾Hide ▴
Evidence considered
  • ClinVar: 1 submission as VUS (Labcorp/Invitae). No expert panel review or phenotype details.
Still missing
  • No proband phenotype or clinical context available.
Sources
clinvar ↗
PP5 PP5 requires a reputable source (e.g., clinical diagnostic laboratory with expertise) to have classified the variant as pathogenic. The single ClinVar submission from Labcorp/Invitae classifies this variant as Uncertain Significance, not Pathogenic. The eight PMIDs associated with this ClinVar record (20301399, 23519317, 23788249, 25356965, 27854360, 34012068, 35802134, 28492532) are all guideline/background papers or a GeneReviews entry; none mention NM_000548.5:c.97G>C specifically and thus cannot support PP5. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: VUS (not P/LP). No reputable source classifies this variant as pathogenic. Associated PMIDs are general guidelines/background
  • not variant-specific evidence.
Sources
clinvar ↗2030139923519317237882492535696527854360340120683580213428492532
BA1 BA1 requires allele frequency above 1% in population databases. NM_000548.5:c.97G>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, not >1%. Details ▾Hide ▴
Evidence considered
  • Allele frequency: 0.0% across all gnomAD datasets.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 BS1 requires allele frequency above 0.3% in population databases. The variant is absent from all queried gnomAD datasets (v2.1, v4.1, Canada). Allele frequency is 0%, not >0.3%. Details ▾Hide ▴
Evidence considered
  • Allele frequency: 0.0% across all gnomAD datasets.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 No observations of NM_000548.5:c.97G>C in healthy adults have been reported. The variant is absent from all population databases, and no literature reports describe its presence in unaffected individuals with full penetrance expected at an early age. Details ▾Hide ▴
Evidence considered
  • No observation in healthy adults
  • variant is absent from population databases.
Still missing
  • No data on variant presence in healthy adult cohorts.
BS3 No well-established in vitro or in vivo functional studies demonstrate that NM_000548.5:c.97G>C has no damaging effect on protein function or splicing. OncoKB shows Unknown Oncogenic Effect without reviewed functional data for this variant. Details ▾Hide ▴
Evidence considered
  • No functional study tests c.97G>C. OncoKB: Unknown Oncogenic Effect
  • not reviewed.
Still missing
  • No functional data demonstrating normal protein function.
Sources
oncokb ↗
BS4 No evidence of non-segregation with disease in affected families has been reported. No family studies involving NM_000548.5:c.97G>C were identified. Details ▾Hide ▴
Evidence considered
  • No segregation or non-segregation data available.
Still missing
  • No family data to assess segregation patterns.
BP1 BP1 applies when a missense variant occurs in a gene where truncating variants are the primary/only known disease mechanism. TSC2 is associated with both truncating and pathogenic missense variants; Tuberous Sclerosis Complex can result from missense changes with functional impact. BP1 is not applicable to TSC2 missense variants in the absence of evidence that missense changes are not a disease mechanism. Details ▾Hide ▴
Evidence considered
  • TSC2 has both truncating and missense pathogenic variants reported
  • missense is a known disease mechanism in TSC2.
BP2 No evidence that NM_000548.5:c.97G>C has been observed in trans with a known pathogenic TSC2 variant, or in cis with a pathogenic variant in this autosomal dominant disorder. Exploratory search found no co-occurrence data. Details ▾Hide ▴
Evidence considered
  • No observation of co-occurrence with a known pathogenic TSC2 variant in cis or trans.
Still missing
  • No co-occurrence data available.
BP5 BP5 requires a reputable source to have classified the variant as benign or to report it as found in a case with an alternate molecular basis for disease. Only one ClinVar submission exists (Labcorp/Invitae, VUS), which classifies the variant as Uncertain Significance, not Benign. Details ▾Hide ▴
Evidence considered
  • ClinVar: single VUS submission. No reputable source classifies this as benign.
Sources
clinvar ↗
BP6 No reputable source (e.g., ClinGen Expert Panel, professional society guideline) has classified NM_000548.5:c.97G>C as benign. The only ClinVar submission is a single clinical laboratory VUS. Details ▾Hide ▴
Evidence considered
  • No expert panel or reputable source classifies this variant as benign.
Sources
clinvar ↗

Not assessed · 2 · no assessment recorded

PS1 No evidence was identified that the same amino acid change (p.Gly33Arg) has been established as pathogenic via a different nucleotide change. No literature or database entry supports a PS1 determination. Details ▾Hide ▴
Evidence considered
  • No prior pathogenic assertion for G33R via an alternate nucleotide change was found.
Still missing
  • No same-amino-acid pathogenic comparator identified in ClinVar
  • literature
  • or databases.
PP2 PP2 applies when a missense variant occurs in a gene with a low rate of benign missense variation and where missense is a common disease mechanism. No gnomAD constraint metrics (Z-score, oe ratio) or HCI prior score are available for TSC2 to assess the rate of benign missense variation. This criterion cannot be assessed without gene-level constraint data. Details ▾Hide ▴
Evidence considered
  • HCI prior data not available for TSC2. No gnomAD missense constraint Z-score available in evidence packet.
Still missing
  • Gene-level missense constraint data (gnomAD Z-score
  • oe ratio) needed for PP2 assessment.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000548.5:c.97G>C is a missense variant (p.Gly33Arg). PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice site). This variant falls outside the PVS1 null-variant buckets per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • c.97G>C is a missense substitution
  • not a nonsense
  • frameshift
  • or canonical splice variant.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/ATSC2-associated Tuberous Sclerosis Complex is an autosomal dominant disorder. PM3 applies only to recessive disorders where the variant is observed in trans with a known pathogenic variant. Details ▾Hide ▴
Evidence considered
  • Tuberous Sclerosis Complex is autosomal dominant
  • PM3 is not applicable.
PM4 N/ANM_000548.5:c.97G>C is a single-nucleotide missense substitution. PM4 applies only to in-frame deletions/insertions or stop-loss variants that alter protein length. Details ▾Hide ▴
Evidence considered
  • c.97G>C is a missense substitution
  • not an in-frame indel or stop-loss variant.
PM5 N/ANo same-residue comparator P/LP missense variants were identified at codon Gly33. The automated PM5 candidate harvest found zero candidates; same-residue PM5 semantics could not be confirmed. No alternative amino acid change at codon 33 has been reported as pathogenic. Details ▾Hide ▴
Evidence considered
  • No P/LP missense variants at TSC2 codon 33 identified in ClinVar or other sources.
Still missing
  • No comparator variant at the same residue.
Sources
pm5_candidates
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without a known function. NM_000548.5:c.97G>C is a single-nucleotide missense substitution, not an in-frame indel. Details ▾Hide ▴
Evidence considered
  • c.97G>C is a missense substitution
  • not an in-frame indel in a repetitive region.
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence or splicing efficiency. NM_000548.5:c.97G>C is a missense variant (p.Gly33Arg), not synonymous. Details ▾Hide ▴
Evidence considered
  • c.97G>C is a missense variant (G>A)
  • not a synonymous variant.
PS5 N/APS5 is not a standard ACMG/AMP criterion. The comparable criterion is PM5 (different missense at same residue as a known pathogenic variant). See PM5 assessment. Details ▾Hide ▴
Evidence considered
  • PS5 is not part of the standard ACMG/AMP 2015 criteria
  • PM5 is the correct criterion.

Identifiers

Gene
TSC2
Transcript
NM_000548.5
Coding (HGVS c.)
NM_000548.5:c.97G>C
Protein (HGVS p.)
NP_000539.2:p.(Gly33Arg)
GRCh38
chr16:2048712 G>C
GRCh37
chr16:2098713 G>C
ClinVar
4802827

Gene diagram

Every interpreted variant in TSC2, mapped onto the exon structure of NM_000548.5. Select a row to find it on the plot.

TSC2NM_000548.5
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.030
Pangolin splice gain
0.090

Other predictors

REVEL
0.212
BayesDel
0.118

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.212 (below 0.5 pathogenic threshold). BayesDel score is 0.118 (low). SpliceAI predicts no splicing alteration (max delta score = 0.00). All three in silico predictors are concordant in not supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.212. BayesDel: 0.118. SpliceAI: max delta 0.00. All predictors concordant for no damaging effect.
Sources
revelbayesdelspliceai ↗
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.212 (well below the 0.5 threshold). BayesDel score is 0.118 (low, not supporting pathogenicity). SpliceAI predicts no splice impact (max delta score = 0.00). The variant does not lie in a known functional domain or hotspot. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.212. BayesDel: 0.118. SpliceAI max delta: 0.00. No in silico predictor supports a damaging effect.
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence or splicing efficiency. NM_000548.5:c.97G>C is a missense variant (p.Gly33Arg), not synonymous. Details ▾Hide ▴
Evidence considered
  • c.97G>C is a missense variant (G>A)
  • not a synonymous variant.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.212. BayesDel score = 0.118026.

8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Tuberous Sclerosis Complex.
    Adam MP et al. · 1993
    No paper-specific finding is recorded.
    PMID 20301399 ↗
  • Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions.
    Schaefer GB et al. · 2013
    No paper-specific finding is recorded.
    PMID 23519317 ↗
  • ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
    Green RC et al. · 2013
    No paper-specific finding is recorded.
    PMID 23788249 ↗
  • ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.
    ACMG Board of Directors · 2015
    No paper-specific finding is recorded.
    PMID 25356965 ↗
  • 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.
    Kalia SS et al. · 2017
    No paper-specific finding is recorded.
    PMID 27854360 ↗
  • 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).
    Miller DT et al. · 2021
    No paper-specific finding is recorded.
    PMID 34012068 ↗
  • 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).
    Miller DT et al. · 2022
    No paper-specific finding is recorded.
    PMID 35802134 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    No paper-specific finding is recorded.
    PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 1 Uncertain significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

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

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.212. BayesDel score = 0.118026.

Functional

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.