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TSC2c.3715G>CUncertain significance
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Variant interpretation report

TSC2 c.3715G>C, p.(Glu1239Gln)

NM_000548.4:c.3715G>C NP_000539.2:p.(Glu1239Gln) 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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting

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%).

PP3Supporting
PP3 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

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, PP3 supporting; combination = 2 supporting, 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.

SpliceAI score
0.050 maximum delta

Recorded SpliceAI maximum delta score: 0.050. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

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 · 20 not met · 1 not assessed · 6 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

This variant is absent from all gnomAD population databases (v2.1, v4.1, and Canada), meeting PM2 at supporting strength.

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.

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.

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.

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).

Met · 2

PM2 SupportingThis 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%). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes).
  • Absent from gnomAD v4.1 (exomes).
  • Absent from gnomAD-Canada v1.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP3 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.577 (damaging).
  • BayesDel score: 0.312735 (damaging range).
Sources
revelbayesdel

Not met · 20 · evaluated, threshold not reached

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. Details ▾Hide ▴
Evidence considered
  • ClinVar has no exact match for this variant
  • no same-amino-acid pathogenic comparator identified.
Still missing
  • No same-residue pathogenic variants with a different nucleotide change identified.
Sources
clinvar ↗
PS2 No de novo data are available for this variant. PubMed and ClinVar do not contain any report of de novo occurrence with confirmed parentage. Details ▾Hide ▴
Evidence considered
  • No de novo reports in ClinVar or literature.
Still missing
  • No family studies or trio sequencing data available.
Sources
clinvar ↗
PS3 No variant-specific functional studies were identified. OncoKB reports unknown oncogenic effect; no COSMIC entries; no publications with variant-specific functional data. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect. No functional studies in literature.
Still missing
  • No functional characterization of the p.Glu1239Gln substitution
  • no systematic mutagenesis data spanning residue 1239.
Sources
oncokb ↗
PS4 No case-control or prevalence data demonstrating enrichment of this variant in affected individuals versus controls. The only associated publication (PMID:25394175) is a general cancer genetics referral guideline that does not mention this variant. Details ▾Hide ▴
Evidence considered
  • No variant-specific case observations in any reviewed source.
Still missing
  • No case-control studies or cohort data for this variant.
Sources
PMID:25394175 ↗
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. Details ▾Hide ▴
Evidence considered
  • Cancerhotspots.org: residue not significant. No domain-level evidence for residue 1239 in a critical functional domain.
Still missing
  • No TSC2 domain map with functional characterization of the region around residue 1239 available in case materials.
PM6 No de novo observation reported for this variant; no evidence of de novo occurrence without confirmation of paternity and maternity. Details ▾Hide ▴
Evidence considered
  • No de novo submissions in ClinVar or literature.
Still missing
  • No trio data or de novo screening available.
Sources
clinvar ↗
PP1 No co-segregation data are available for this variant. No family studies were identified. Details ▾Hide ▴
Evidence considered
  • No segregation data in any reviewed source.
Still missing
  • No family studies or co-segregation analysis.
PP2 HCI prior score not available for TSC2; cannot assess whether TSC2 has a low rate of benign missense variation. Insufficient data to apply PP2. Details ▾Hide ▴
Evidence considered
  • HCI prior lookup returned: gene not supported.
Still missing
  • No missense constraint metric available for TSC2.
PP5 No reputable source has classified this variant as pathogenic. ClinVar has no exact match; the closest candidate is a different variant classified as VUS. The associated PMID (25394175) is a general cancer genetics referral guideline that does not mention this specific variant. Details ▾Hide ▴
Evidence considered
  • ClinVar: no exact match
  • closest candidate is a different variant (p.Val1299Leu) classified VUS.
  • PMID:25394175 does not mention this variant
  • it is a general ACMG/NSGC practice guideline about cancer referral indications.
Still missing
  • No expert panel classification or reputable source classification for this variant.
Sources
clinvar ↗PMID:25394175 ↗
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%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • v4.1
  • and Canada.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 This variant is absent from gnomAD and does not exceed the BS1 allele frequency threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD
  • allele frequency does not exceed 0.3%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 No evidence that this variant has been observed in a healthy adult individual. gnomAD shows complete absence from population databases. Details ▾Hide ▴
Evidence considered
  • No observation in any population database
  • no healthy adult carrier data.
Still missing
  • No clinical cohort data for healthy adult carriers.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No functional studies demonstrating a benign or neutral effect of the p.Glu1239Gln substitution were identified. No experimental characterization of this variant exists. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect. No functional studies demonstrating benign effect.
Still missing
  • No functional characterization of this variant.
Sources
oncokb ↗
BS4 No segregation data are available to assess lack of co-segregation with disease. No family studies identified. Details ▾Hide ▴
Evidence considered
  • No segregation or family study data available.
Still missing
  • No family studies or co-segregation analysis.
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. Details ▾Hide ▴
Evidence considered
  • TSC2 loss-of-function is an established disease mechanism
  • but both missense and truncating variants are known to cause TSC.
Sources
pvs1_gene_context
BP2 No data regarding observation of this variant in trans with a known pathogenic TSC2 variant. TSC2 disease is autosomal dominant; biallelic in trans observations are not expected in the typical disease context. Details ▾Hide ▴
Evidence considered
  • No in trans data available.
Still missing
  • No phase data for any co-occurring TSC2 variants.
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. SpliceAI max delta 0.05 indicates no splicing impact but does not provide evidence of a benign effect for a missense variant. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.577 (damaging).
  • BayesDel: 0.312735 (damaging range).
  • SpliceAI: 0.05 (no splicing impact
  • neutral for splicing only).
Sources
revelbayesdelspliceai ↗
BP5 No alternative molecular basis for disease has been identified in this case. BP5 requires an established alternative cause, which has not been demonstrated. Details ▾Hide ▴
Evidence considered
  • No alternative molecular cause identified in case materials.
Still missing
  • No data on whether an alternative genetic diagnosis has been established for this patient.
BP6 No reputable source has classified this variant as benign. ClinVar has no exact match for this variant; the closest candidate is a different variant classified as VUS. Details ▾Hide ▴
Evidence considered
  • No exact ClinVar match
  • no benign classification from any reputable source.
Still missing
  • No expert panel or reputable benign classification.
Sources
clinvar ↗
PS5 No established pathogenic variant from a reputable source. The closest ClinVar candidate (NM_000548.5:c.3895G>C, p.Val1299Leu) is a different variant classified as uncertain significance by a single submitter (Ambry Genetics). Details ▾Hide ▴
Evidence considered
  • ClinVar closest match is a non-exact
  • different variant classified as VUS.
Still missing
  • No expert panel or reputable source classification for this variant.
Sources
clinvar ↗

Not assessed · 1 · no assessment recorded

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. Details ▾Hide ▴
Evidence considered
  • No patient phenotype data provided.
Still missing
  • Patient phenotype and clinical history not available for this case.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000548.4:c.3715G>C is a missense substitution (p.Glu1239Gln) and does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per PMC6185798. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not a predicted null variant.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/ATSC2-related disease is autosomal dominant; PM3 (recessive disorder trans observation) is not applicable. Details ▾Hide ▴

No further detail was recorded.

PM4 N/ANot a protein-length-altering variant (non-frameshift indel, stop-loss, or initiation codon change); PM4 does not apply to missense substitutions. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo same-residue pathogenic missense comparator variants identified in ClinVar; automated candidate harvesting could not confirm classic PM5 semantics. Details ▾Hide ▴
Evidence considered
  • Zero same-residue candidates with expert panel pathogenic classification.
Sources
pm5_candidates
BP3 N/ANot an in-frame deletion or insertion in a non-repeat region; BP3 does not apply to missense substitutions. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ANM_000548.4:c.3715G>C is a missense variant (p.Glu1239Gln), not a synonymous or intronic variant. BP7 does not apply. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • BP7 is specific to synonymous and intronic variants outside splice sites.
Sources
spliceai ↗

Identifiers

Gene
TSC2
Transcript
NM_000548.4
Coding (HGVS c.)
NM_000548.4:c.3715G>C
Protein (HGVS p.)
NP_000539.2:p.(Glu1239Gln)
GRCh38
chr16:2081699 G>C
GRCh37
chr16:2131700 G>C
ClinVar
3811357, 999086

Gene diagram

Every interpreted variant in TSC2, mapped onto the exon structure of NM_000548.4. Select a row to find it on the plot.

TSC2NM_000548.4
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

SpliceAI acceptor lossat -27 bp
0.010
SpliceAI acceptor gainat +3 bp
0.050
SpliceAI donor lossat +417 bp
0.000
SpliceAI donor gainat -391 bp
0.000
Pangolin splice lossmagnitude shown
-0.020
Pangolin splice gain
0.000

Other predictors

REVEL
0.577
BayesDel
0.313

How the predictions were used

PP3 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.577 (damaging).
  • BayesDel score: 0.312735 (damaging range).
Sources
revelbayesdel
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. SpliceAI max delta 0.05 indicates no splicing impact but does not provide evidence of a benign effect for a missense variant. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.577 (damaging).
  • BayesDel: 0.312735 (damaging range).
  • SpliceAI: 0.05 (no splicing impact
  • neutral for splicing only).
Sources
revelbayesdelspliceai ↗
BP7 N/ANM_000548.4:c.3715G>C is a missense variant (p.Glu1239Gln), not a synonymous or intronic variant. BP7 does not apply. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • BP7 is specific to synonymous and intronic variants outside splice sites.
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.577. BayesDel score = 0.312735.

1 paper record 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

  • 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. · 2015
    This is a general practice guideline from ACMG and NSGC providing referral indications for cancer predisposition assessment. It mentions Tuberous Sclerosis Complex (TSC) in tables as one of many hereditary cancer syndromes with referral criteria. NM_000548.4:c.3715G>C was not identified in this paper.
    Does not name this variant
    PMID 25394175 ↗

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 0.050 Open source ↗
ClinVar Captured ClinVar source record 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 is absent from ClinVar.

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

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.