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TSC2c.981G>TUncertain significance
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Variant interpretation report

TSC2 c.981G>T, p.(Met327Ile)

NM_000548.4:c.981G>T NP_000539.2:p.(Met327Ile) 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: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting PM2 at supporting strength under generic ACMG/AMP 2015 guidelines for variants absent from population databases.

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; combination = 1 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
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied 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: 1 met · 22 not met · 2 not assessed · 4 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_000548.4:c.981G>T (p.Met327Ile) is a missense variant in TSC2, a gene in which germline pathogenic variants cause tuberous sclerosis complex (autosomal dominant).

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

The variant is absent from ClinVar and has not been reported in the literature as pathogenic or benign.

In silico predictions are indeterminate: REVEL score is 0.333 (not clearly pathogenic or benign), BayesDel is 0.107, and SpliceAI predicts no splicing impact (max delta 0.01). PP3 and BP4 are not met.

No functional studies, segregation data, de novo reports, or case-control studies are available for this variant.

Under generic ACMG/AMP 2015 guidelines, only PM2 (supporting) is met, which is insufficient to classify this variant as likely pathogenic or pathogenic.

This variant is classified as a Variant of Uncertain Significance (VUS).

Met · 1

PM2 SupportingThis variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting PM2 at supporting strength under generic ACMG/AMP 2015 guidelines for variants absent from population databases. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles).
  • Absent from gnomAD v4.1 (0 alleles).
  • Absent from gnomAD-Canada v1.0 (0 alleles).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 22 · evaluated, threshold not reached

PVS1 This variant is a missense substitution (p.Met327Ile) and does not fall into the null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for PVS1 under the ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution (c.981G>T
  • p.Met327Ile)
  • not a predicted null variant.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS2 No de novo occurrence data with confirmed parentage is available for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified.
Still missing
  • No family trio data available.
PS3 No well-established in vitro or in vivo functional studies demonstrating a damaging effect have been identified for this variant. OncoKB classifies this variant as Unknown Oncogenic Effect. Details ▾Hide ▴
Evidence considered
  • OncoKB reports Unknown Oncogenic Effect for p.M327I.
  • No variant-specific functional studies found in the reviewed literature.
Still missing
  • No functional characterization of p.Met327Ile available.
Sources
oncokb ↗
PS4 The variant is absent from population databases, and no case-control studies or case series demonstrating significant enrichment in affected individuals have been identified. The literature reviewed consists of clinical practice guidelines that do not report individual variant observations. Details ▾Hide ▴
Evidence considered
  • No case observations or cohort data for this variant.
Still missing
  • No published case reports or cohort studies.
Sources
PMID:9536098 ↗PMID:23519317 ↗PMID:25356965 ↗PMID:27854360 ↗PMID:35802134 ↗
PM1 This variant (p.Met327Ile) does not lie within a statistically significant mutational hotspot, and there is no evidence that codon 327 resides in a critical functional domain without benign variation. Details ▾Hide ▴
Evidence considered
  • No statistically significant hotspot at position 327.
  • No domain-level constraint data available.
Still missing
  • No TSC2 domain-specific constraint data available.
PM6 No de novo observation (with or without confirmed parentage) has been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified.
Still missing
  • No family trio data available.
PP1 No co-segregation data in affected family members is available for this variant. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • No family studies available.
PP2 While TSC2 is a known tumor suppressor gene in which missense variants can be pathogenic, HCI prior probability data was not available for this gene, and no formal missense constraint metric (e.g., Z-score) was obtained to support PP2 under generic ACMG/AMP 2015. Details ▾Hide ▴
Evidence considered
  • HCI prior data not found for TSC2.
Still missing
  • No TSC2 missense constraint metric (Z-score) available for PP2 assessment.
PP3 In silico predictions do not consistently support a deleterious effect. REVEL score is 0.333 (indeterminate range, below typical pathogenic threshold of 0.5), BayesDel score is 0.107 (below pathogenic threshold), and SpliceAI predicts no splicing impact (max delta score 0.01). Multiple lines of computational evidence do not collectively support pathogenicity. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.333 (indeterminate).
  • BayesDel: 0.107 (below pathogenic threshold).
  • SpliceAI: max delta 0.01 (no splicing impact).
Sources
revelbayesdelspliceai ↗
PP4 No patient phenotype or family history data is available to assess whether the clinical presentation is highly specific for TSC2-related disease. Details ▾Hide ▴
Evidence considered
  • No patient phenotype data provided.
Still missing
  • No clinical phenotype information available for the proband.
PP5 This variant is absent from ClinVar and has not been reported as pathogenic by any reputable source. The ACMG SF guideline papers list TSC2 as an actionable gene for secondary findings but do not assess or report this specific variant. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar.
  • No reputable source reports this variant as pathogenic.
Sources
clinvar ↗PMID:23519317 ↗PMID:25356965 ↗PMID:27854360 ↗PMID:35802134 ↗
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, well below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • Allele frequency = 0% in all gnomAD datasets.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant is absent from population databases. Allele frequency is 0%, well below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • Allele frequency = 0% in all gnomAD datasets.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No data are available regarding observation of this variant in healthy adult individuals. The variant is absent from all population databases, precluding BS2 assessment. Details ▾Hide ▴
Evidence considered
  • No healthy adult observations available.
Still missing
  • No population screening data for healthy adults available.
BS3 No well-established functional studies demonstrating no damaging effect have been identified for this variant. OncoKB reports Unknown Oncogenic Effect for p.M327I. Details ▾Hide ▴
Evidence considered
  • No functional studies demonstrating benign effect available.
Still missing
  • No functional characterization of p.Met327Ile available.
Sources
oncokb ↗
BS4 No family segregation data are available to assess lack of segregation with disease. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • No family studies available.
BP1 TSC2 is not a gene in which ONLY truncating variants cause disease. Pathogenic missense variants in TSC2 are well-established in tuberous sclerosis complex. Details ▾Hide ▴
Evidence considered
  • TSC2 has established pathogenic missense variants.
BP2 No data are available regarding observation of this variant in trans with a known pathogenic variant for tuberous sclerosis complex. Details ▾Hide ▴
Evidence considered
  • No trans-configuration data available.
Still missing
  • No co-occurrence data available.
BP4 Computational evidence is mixed rather than consistently benign. REVEL score is 0.333 (indeterminate), BayesDel is 0.107 (slightly below typical thresholds), and SpliceAI shows no splicing impact. The in silico evidence does not provide multiple consistent lines supporting a benign effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.333 (indeterminate
  • not clearly benign).
  • BayesDel: 0.107.
  • SpliceAI: max delta 0.01 (no splicing impact).
Sources
revelbayesdelspliceai ↗
BP5 No data are available regarding observation of this variant in a case with an alternative molecular basis for disease. Details ▾Hide ▴
Evidence considered
  • No alternative molecular diagnosis data available.
Still missing
  • No data on co-occurring pathogenic variants.
BP6 This variant is absent from ClinVar and has not been reported as benign by any reputable source. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar.
  • No reputable source reports this variant as benign.
Sources
clinvar ↗
BP7 This variant is a missense substitution (p.Met327Ile), not a synonymous variant. BP7 does not apply. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous.

Not assessed · 2 · no assessment recorded

PS1 No prior pathogenic variant at the same amino acid position (p.Met327) with the same amino acid change has been identified in ClinVar or the reviewed literature. Details ▾Hide ▴
Evidence considered
  • No known pathogenic variant at codon 327 in TSC2.
Still missing
  • No systematic search for same-residue pathogenic variants beyond ClinVar.
Sources
clinvar ↗
PS5 PS5 is not part of the generic ACMG/AMP 2015 framework (Richards et al., PMID:25741868). No framework-specific rule is available for this criterion. Details ▾Hide ▴
Evidence considered
  • Criterion not applicable to generic ACMG 2015.
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/APM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant; not applicable to this autosomal dominant TSC2 variant. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to protein-length-altering changes (in-frame deletions/insertions, stop-loss); not applicable to this missense substitution. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo pathogenic missense comparator at the same residue (p.Met327) with a different amino acid change was identified. PM5 candidate search returned no same-residue candidates in ClinVar. Details ▾Hide ▴
Evidence considered
  • No same-residue pathogenic missense variants identified.
Sources
pm5_candidates
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; not applicable to a missense substitution. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
TSC2
Transcript
NM_000548.4
Coding (HGVS c.)
NM_000548.4:c.981G>T
Protein (HGVS p.)
NP_000539.2:p.(Met327Ile)
GRCh38
chr16:2060675 G>T
GRCh37
chr16:2110676 G>T
ClinVar
2760443, 2112035

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 -76 bp
0.010
SpliceAI acceptor gainat +16 bp
0.010
SpliceAI donor lossat +138 bp
0.000
SpliceAI donor gainat +364 bp
0.000
Pangolin splice lossmagnitude shown
-0.030
Pangolin splice gain
0.010

Other predictors

REVEL
0.333
BayesDel
0.107

How the predictions were used

PP3 In silico predictions do not consistently support a deleterious effect. REVEL score is 0.333 (indeterminate range, below typical pathogenic threshold of 0.5), BayesDel score is 0.107 (below pathogenic threshold), and SpliceAI predicts no splicing impact (max delta score 0.01). Multiple lines of computational evidence do not collectively support pathogenicity. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.333 (indeterminate).
  • BayesDel: 0.107 (below pathogenic threshold).
  • SpliceAI: max delta 0.01 (no splicing impact).
Sources
revelbayesdelspliceai ↗
BP4 Computational evidence is mixed rather than consistently benign. REVEL score is 0.333 (indeterminate), BayesDel is 0.107 (slightly below typical thresholds), and SpliceAI shows no splicing impact. The in silico evidence does not provide multiple consistent lines supporting a benign effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.333 (indeterminate
  • not clearly benign).
  • BayesDel: 0.107.
  • SpliceAI: max delta 0.01 (no splicing impact).
Sources
revelbayesdelspliceai ↗
BP7 This variant is a missense substitution (p.Met327Ile), not a synonymous variant. BP7 does not apply. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.333. BayesDel score = 0.107074.

5 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

  • Statistical features of human exons and their flanking regions.
    Zhang MQ · 1998
    Comprehensive survey of statistical features of human exons and flanking regions, including splicing signals, codon usage, and nucleotide composition. NM_000548.4:c.981G>T was not identified in this paper.
    Does not name this variant
    PMID 9536098 ↗
  • Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions.
    Schaefer GB et al. · 2013
    ACMG practice guideline for clinical genetics evaluation of autism spectrum disorders, discussing chromosomal microarray, fragile X, MECP2, and PTEN testing. NM_000548.4:c.981G>T was not identified in this paper.
    Does not name this variant
    PMID 23519317 ↗
  • ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.
    ACMG Board of Directors · 2015
    ACMG policy statement updating recommendations for secondary findings in clinical genome-scale sequencing, focused on the opt-out consent process. NM_000548.4:c.981G>T was not identified in this paper.
    Does not name this variant
    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
    ACMG SF v2.0 policy statement updating the minimum list of genes for secondary findings in clinical exome/genome sequencing. TSC2 is listed among genes recommended for return of secondary findings for Tuberous Sclerosis Complex, but the specific variant NM_000548.4:c.981G>T is not mentioned.
    Does not name this variant
    PMID 27854360 ↗
  • 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
    ACMG SF v3.1 policy statement updating the secondary findings gene list. TSC2 is listed among genes recommended for return of secondary findings for Tuberous Sclerosis Complex, but the specific variant NM_000548.4:c.981G>T is not mentioned.
    Does not name this variant
    PMID 35802134 ↗

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 0.010 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 = 0.01). REVEL score = 0.333. BayesDel score = 0.107074.

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.