About TSC2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TSC2 c.5186G>A, p.(Arg1729His)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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.5186G>A is present at very low frequency in population databases: gnomAD v2.1 allele frequency 0.00607% (17/280,130 alleles, 0 homozygotes) and gnomAD v4.1 allele frequency 0.00355% (57/1,604,608 alleles, 0 homozygotes). Both frequencies are below the 0.1% PM2 threshold for rare disease variants. Absent from gnomAD-Canada v1.0.
Benign criteria applied · 1
BP6Supporting
BP6 · supporting
NM_000548.5:c.5186G>A has been classified as Likely benign by GeneDx, Ambry Genetics, and Labcorp Genetics (formerly Invitae), and as Benign by Genome-Nilou Lab and an additional clinical laboratory, for a total of 5 clinical diagnostic laboratories reporting benign or likely benign without shared internal data. This meets BP6 at supporting benign strength.
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, BP6 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
57 / 1,604,608 alleles
gnomAD v4.1: 57 / 1,604,608 alleles. Recorded AF 3.55227e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.06861e-05; MAF= 0.00607%, 17/280130 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000254266; MAF= 0.02543%, 9/35396 alleles, homozygotes = 0); grpmax FAF= 0.00013485.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
7 reported laboratory submissions
3 Likely benign · 2 Benign · 2 Uncertain significance.
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
3 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV51911686, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 9 not met · 12 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000548.5:c.5186G>A (p.Arg1729His) in TSC2 is a missense variant in exon 41. PVS1 is not applicable as this is not a null variant.
This variant is present at very low frequency in gnomAD v2.1 (AF=0.00607%, 17/280,130 alleles) and gnomAD v4.1 (AF=0.00355%, 57/1,604,608 alleles), with no homozygotes observed, meeting PM2 at supporting strength.
This variant has been classified as Likely benign by three clinical laboratories (GeneDx, Ambry Genetics, Labcorp Genetics) and as Benign by two clinical laboratories in ClinVar (variation ID 207786), meeting BP6 at supporting benign strength.
In silico predictions are conflicting: REVEL score is 0.811 (damaging) while BayesDel score is 0.179 (benign) and SpliceAI predicts no splice impact (max delta 0.00). Neither PP3 nor BP4 can be applied due to mixed computational evidence.
No variant-specific functional studies, de novo observations, cosegregation data, or case-control evidence were identified for NM_000548.5:c.5186G>A in the reviewed literature. OncoKB reports Unknown Oncogenic Effect.
No pathogenic classification was reported by any ClinVar submitter. PS5 and PP5 are not met.
Allele frequency does not meet BA1 (>1%) or BS1 (>0.3%) thresholds. No homozygotes have been observed, so BS2 is not met.
With PM2 (supporting pathogenic) and BP6 (supporting benign) as the only scorable criteria, these opposing supporting-level criteria effectively neutralize each other. The variant remains a Variant of Uncertain Significance under generic ACMG/AMP 2015 rules.
No criteria match.
Met · 2
PM2 SupportingNM_000548.5:c.5186G>A is present at very low frequency in population databases: gnomAD v2.1 allele frequency 0.00607% (17/280,130 alleles, 0 homozygotes) and gnomAD v4.1 allele frequency 0.00355% (57/1,604,608 alleles, 0 homozygotes). Both frequencies are below the 0.1% PM2 threshold for rare disease variants. Absent from gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.00607% (17/280
- 130 alleles). gnomAD v4.1: AF=0.00355% (57/1
- 604
- 608 alleles). Both <0.1%. No homozygotes. Absent from gnomAD-Canada.
Sources
BP6 SupportingNM_000548.5:c.5186G>A has been classified as Likely benign by GeneDx, Ambry Genetics, and Labcorp Genetics (formerly Invitae), and as Benign by Genome-Nilou Lab and an additional clinical laboratory, for a total of 5 clinical diagnostic laboratories reporting benign or likely benign without shared internal data. This meets BP6 at supporting benign strength. Details ▾Hide ▴
Evidence considered
- ClinVar variation 207786: Likely benign by 3 clinical laboratories (GeneDx
- Ambry Genetics
- Labcorp Genetics)
- Benign by 2 clinical laboratories. Review status: criteria provided
- single submitter. No expert panel review.
Sources
Not met · 9 · evaluated, threshold not reached
PS3 No variant-specific functional evidence was identified for p.Arg1729His. OncoKB reports Unknown Oncogenic Effect for this variant, and no reviewed publication contained functional data for NM_000548.5:c.5186G>A. Details ▾Hide ▴
Evidence considered
- OncoKB classifies this variant as Unknown Oncogenic Effect. No functional studies of p.Arg1729His were identified in the literature.
Still missing
- No well-established functional assay data available for this specific variant.
Sources
PP3 In silico predictions are conflicting. REVEL score is 0.811 (damaging), but BayesDel score is 0.178539 (benign). SpliceAI max delta is 0.00 (no predicted splice impact). Multiple lines of computational evidence do not consistently support a deleterious effect on the gene or gene product. Details ▾Hide ▴
Evidence considered
- REVEL: 0.811 (damaging). BayesDel: 0.178539 (benign). SpliceAI: max delta 0.00 (no splice impact). Conflicting in silico predictions.
Sources
PP5 No reputable source has reported NM_000548.5:c.5186G>A as pathogenic. The majority of ClinVar classifications are Likely benign or Benign (5 of 7 clinical laboratory submissions). The ACMG/ClinGen guideline papers cited in ClinVar submissions do not report this specific variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar: Likely benign (3 labs)
- Benign (2 labs)
- VUS (2 labs). No pathogenic classification from any submitter.
Sources
BA1 NM_000548.5:c.5186G>A allele frequency in gnomAD v2.1 (0.00607%) and v4.1 (0.00355%) is far below the 1% BA1 threshold. Does not meet BA1. Details ▾Hide ▴
BS1 NM_000548.5:c.5186G>A allele frequency in gnomAD v2.1 (0.00607%) and v4.1 (0.00355%) is far below the 0.3% BS1 threshold. Does not meet BS1. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.00607%
- v4.1 AF=0.00355%
- both <<0.3%.
Sources
BS2 No homozygotes for NM_000548.5:c.5186G>A are observed in gnomAD v2.1 or v4.1. BS2 requires observation in a homozygous state in healthy adults; no such observation has been documented. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0 homozygotes. gnomAD v4.1: 0 homozygotes. No observation of homozygous healthy adults.
Sources
BS3 No well-established functional studies demonstrating no deleterious effect were identified for NM_000548.5:c.5186G>A. OncoKB reports Unknown Oncogenic Effect and no reviewed publication contained variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect. No variant-specific functional studies identified in literature.
Still missing
- No functional assay data for p.Arg1729His.
Sources
BP4 In silico predictions are conflicting. While SpliceAI predicts no splice impact (max delta 0.00) and BayesDel score (0.179) is in the benign range, REVEL score is 0.811 (damaging). Multiple lines of computational evidence do not consistently support a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.811 (damaging). BayesDel: 0.178539 (benign). SpliceAI: max delta 0.00 (no splice impact). Conflicting predictions preclude BP4.
Sources
PS5 No reputable source has recently reported NM_000548.5:c.5186G>A as pathogenic. ClinVar submissions are predominantly Likely benign (3 laboratories) and Benign (2 laboratories), with 2 Uncertain significance submissions; no pathogenic classification is present. Details ▾Hide ▴
Evidence considered
- ClinVar variation ID 207786: Likely benign (3 labs)
- Benign (2 labs)
- Uncertain significance (2 labs). No pathogenic submissions.
Sources
Not assessed · 12 · no assessment recorded
PS1 No same-amino-acid change comparator variant with established pathogenicity was identified for p.Arg1729His. Insufficient data to assess PS1. Details ▾Hide ▴
Still missing
- No known pathogenic variant with the same amino acid change (Arg1729His) identified in ClinVar or literature.
PS2 No de novo observation data were identified for NM_000548.5:c.5186G>A in any reviewed source. Details ▾Hide ▴
Still missing
- No de novo reports found in ClinVar submissions or literature.
PS4 No case-control or cohort data reporting NM_000548.5:c.5186G>A prevalence in affected individuals were identified. Reviewed publications were guideline/policy statements that did not contain patient-level variant observations. Details ▾Hide ▴
Still missing
- No patient cohort or case-control data available for prevalence comparison.
Sources
25741868203013992351931723788249253569652539417527854360340120683580213428492532
PM1 Residue p.Arg1729 does not lie within a statistically significant cancer hotspot. No domain-level functional evidence was curated for PM1 assessment. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue not significant
- exact variant not listed.
Still missing
- No curated mutational hotspot or critical functional domain data for TSC2 residue 1729.
PM6 No de novo observation data were identified for NM_000548.5:c.5186G>A. PM6 requires a confirmed de novo event with confirmed maternity and paternity. Details ▾Hide ▴
Still missing
- No de novo reports for this variant.
PP1 No cosegregation data were identified for NM_000548.5:c.5186G>A in any reviewed source. Details ▾Hide ▴
Still missing
- No family cosegregation data available.
PP2 Insufficient data to assess TSC2 missense constraint. PP2 requires a gene with a low rate of benign missense variation (high missense Z-score), which was not available in the curated evidence for TSC2. Details ▾Hide ▴
Still missing
- No TSC2 missense constraint metrics (Z-score) available in curated evidence.
PP4 No patient phenotype or family history data were available for NM_000548.5:c.5186G>A to assess specificity for tuberous sclerosis complex. Details ▾Hide ▴
Still missing
- No patient-specific phenotype data available.
BS4 No cosegregation data were available to assess lack of segregation with disease for NM_000548.5:c.5186G>A. Details ▾Hide ▴
Still missing
- No family segregation data available.
BP1 TSC2 is associated with tuberous sclerosis complex through both loss-of-function and missense pathogenic variants. BP1 applies to genes where only truncating variants cause disease; TSC2 has known pathogenic missense variants, so BP1 does not clearly apply. Insufficient curated data to adjudicate definitively. Details ▾Hide ▴
Evidence considered
- TSC2 has both missense and truncating pathogenic variants reported in tuberous sclerosis complex. BP1 applicability is questionable without formal gene-level determination.
Still missing
- No formal gene-level determination of whether missense variants are a confirmed disease mechanism for TSC2 in the curated evidence.
BP2 No data on whether NM_000548.5:c.5186G>A has been observed in trans with a known pathogenic TSC2 variant. TSC2-associated disease follows an autosomal dominant pattern; BP2 is more applicable to recessive disorders. Details ▾Hide ▴
Still missing
- No trans-configuration data available
- limited relevance in autosomal dominant TSC2.
BP5 No data were available on whether NM_000548.5:c.5186G>A was observed in a case with an alternative molecular basis for disease. Details ▾Hide ▴
Still missing
- No alternative molecular basis data available.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000548.5:c.5186G>A is a missense variant (p.Arg1729His) in exon 41 of TSC2. It does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The PVS1 generic framework is not applicable. Details ▾Hide ▴
Evidence considered
- Missense substitution not covered by PVS1 null-variant criteria per ClinGen SVI PVS1 recommendations (PMC6185798).
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM5 N/ANo same-residue comparator variant with established pathogenicity was identified. Automatic candidate harvesting for PM5 was skipped due to inability to confirm classic same-residue PM5 semantics safely. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: no same-residue pathogenic comparator variants found for p.Arg1729.
Sources
pm5_candidates
BP7 N/ANM_000548.5:c.5186G>A is a missense variant (p.Arg1729His), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is a synonymous-variant criterion.
Identifiers
- Gene
- TSC2
- Transcript
- NM_000548.5
- Coding (HGVS c.)
- NM_000548.5:c.5186G>A
- Protein (HGVS p.)
- NP_000539.2:p.(Arg1729His)
- GRCh38
- chr16:2088252 G>A
- GRCh37
- chr16:2138253 G>A
- ClinVar
- 4760845, 381472, 207786
- COSMIC
- COSV51911686
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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in TSC2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
57 / 1,604,608 alleles
AF 3.55e-05 · 0 homozygotes · FAF 6.68e-05
gnomAD v2.1
17 / 280,130 alleles
AF 6.07e-05 · 0 homozygotes · FAF 0.000135
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 3.6e-05 · 57 / 1,604,608 alleles · 0 hom · FAF 6.7e-05
| Admixed American8 / 59,336 | 0.00013 |
| Remaining individuals3 / 62,332 | 4.8e-05 |
| European (non-Finnish)42 / 1,176,864 | 3.6e-05 |
| African/African American2 / 71,874 | 2.8e-05 |
| East Asian1 / 44,460 | 2.2e-05 |
| South Asian1 / 90,834 | 1.1e-05 |
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 6.1e-05 · 17 / 280,130 alleles · 0 hom · FAF 0.00013
| Admixed American9 / 35,396 | 0.00025 |
| Remaining individuals1 / 7,142 | 0.00014 |
| African/African American2 / 24,146 | 8.3e-05 |
| European (non-Finnish)5 / 127,614 | 3.9e-05 |
0 alternate alleles recorded in 4 other groups: Ashkenazi Jewish, East Asian, European (Finnish), South Asian.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.55227e-05; MAF= 0.00355%, 57/1604608 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000134825; MAF= 0.01348%, 8/59336 alleles, homozygotes = 0); grpmax FAF= 6.679e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.06861e-05; MAF= 0.00607%, 17/280130 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000254266; MAF= 0.02543%, 9/35396 alleles, homozygotes = 0); grpmax FAF= 0.00013485.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.811
- BayesDel
- 0.179
How the predictions were used
PP3 In silico predictions are conflicting. REVEL score is 0.811 (damaging), but BayesDel score is 0.178539 (benign). SpliceAI max delta is 0.00 (no predicted splice impact). Multiple lines of computational evidence do not consistently support a deleterious effect on the gene or gene product. Details ▾Hide ▴
Evidence considered
- REVEL: 0.811 (damaging). BayesDel: 0.178539 (benign). SpliceAI: max delta 0.00 (no splice impact). Conflicting in silico predictions.
Sources
BP4 In silico predictions are conflicting. While SpliceAI predicts no splice impact (max delta 0.00) and BayesDel score (0.179) is in the benign range, REVEL score is 0.811 (damaging). Multiple lines of computational evidence do not consistently support a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.811 (damaging). BayesDel: 0.178539 (benign). SpliceAI: max delta 0.00 (no splice impact). Conflicting predictions preclude BP4.
Sources
BP7 N/ANM_000548.5:c.5186G>A is a missense variant (p.Arg1729His), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is a synonymous-variant criterion.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.811. BayesDel score = 0.178539.
9 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
-
PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015No paper-specific finding is recorded.
-
PMID 20301399 ↗Tuberous Sclerosis Complex.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 23519317 ↗Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions.Schaefer GB et al. · 2013No paper-specific finding is recorded.
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PMID 23788249 ↗ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.Green RC et al. · 2013No paper-specific finding is recorded.
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PMID 25356965 ↗ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.ACMG Board of Directors · 2015No paper-specific finding is recorded.
-
PMID 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.Hampel H et al. · 2015No paper-specific finding is recorded.
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PMID 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.Kalia SS et al. · 2017No paper-specific finding is recorded.
-
PMID 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).Miller DT et al. · 2021No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
57 / 1,604,608 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
3 Likely benign · 2 Benign · 2 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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/207786/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-2138253-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-2088252-G-A?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000548.5%3Ac.5186…
- OncoKB ↗www.oncokb.org/gene/TSC2/R1729H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=120482412
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.55227e-05; MAF= 0.00355%, 57/1604608 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000134825; MAF= 0.01348%, 8/59336 alleles, homozygotes = 0); grpmax FAF= 6.679e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.06861e-05; MAF= 0.00607%, 17/280130 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000254266; MAF= 0.02543%, 9/35396 alleles, homozygotes = 0); grpmax FAF= 0.00013485.
ClinVar
This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Benign (2 clinical laboratories) and as Uncertain significance (2 clinical laboratories). (ClinVarID = 207786)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.811. BayesDel score = 0.178539.
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 previously been reported in somatic cancers (COSMIC; COSV51911686, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.