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.1 The variant is absent from ClinVar and has not been reported in the literature as pathogenic or benign.2 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.3 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).
TSC2
Final classification
VUS
TSC2 c.981G>T · p.Met327Ile
TSC2
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).
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.
Classification rationale
PM2
VUS
TSC2 c.981G>T
PM2
→
VUS
Gene diagram
· NM_000548.4 · variants mapped to exon structure
TSC2
NM_000548.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 23 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
Absent from gnomAD v2.1 (0 alleles).Absent from gnomAD v4.1 (0 alleles).Absent from gnomAD-Canada v1.0 (0 alleles).
Assessed · not applied
Pathogenic
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).
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.
PS2
No de novo occurrence data with confirmed parentage is available for this variant.
PS3
No well-established in vitro or in vivo functional studies demonstrating a damaging effect have been identified for this variant.
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.
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.
PM6
No de novo observation (with or without confirmed parentage) has been reported for this variant.
PP1
No co-segregation data in affected family members is available for this variant.
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.
PP3
In silico predictions do not consistently support a deleterious effect.
PP4
No patient phenotype or family history data is available to assess whether the clinical presentation is highly specific for TSC2-related disease.
PP5
This variant is absent from ClinVar and has not been reported as pathogenic by any reputable source.
Benign
BA1
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
The variant is absent from population databases.
BS2
No data are available regarding observation of this variant in healthy adult individuals.
BS3
No well-established functional studies demonstrating no damaging effect have been identified for this variant.
BS4
No family segregation data are available to assess lack of segregation with disease.
BP1
TSC2 is not a gene in which ONLY truncating variants cause disease.
BP2
No data are available regarding observation of this variant in trans with a known pathogenic variant for tuberous sclerosis complex.
BP4
Computational evidence is mixed rather than consistently benign.
BP5
No data are available regarding observation of this variant in a case with an alternative molecular basis for disease.
BP6
This variant is absent from ClinVar and has not been reported as benign by any reputable source.
BP7
This variant is a missense substitution (p.Met327Ile), not a synonymous variant.
N/A · 4
PM3 · PM4 · PM5 · BP3
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
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
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.
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.
Sources & reference links
Triaged references · 5 PMIDs not cited in assessment
23519317 ↗
Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions.
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
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