NM_000548.4:c.981G>T

TSC2 · NP_000539.2:p.(Met327Ile) · NM_000548.4

GRCh37: chr16:2110676 G>T · GRCh38: chr16:2060675 G>T

Gene: TSC2 Transcript: NM_000548.4

Final call

VUS

PM2 supporting

Variant details

Gene

TSC2

Transcript

NM_000548.4

Protein

NP_000539.2:p.(Met327Ile)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	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).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not assessed	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.	clinvar
PS2	Not met	No de novo occurrence data with confirmed parentage is available for this variant.
PS3	Not met	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.	oncokb
PS4	Not met	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.
PS5	Not assessed	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.
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	PM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant; not applicable to this autosomal dominant TSC2 variant.
PM4	N/A	PM4 applies to protein-length-altering changes (in-frame deletions/insertions, stop-loss); not applicable to this missense substitution.
PM5	N/A	No 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.	pm5_candidates
PM6	Not met	No de novo observation (with or without confirmed parentage) has been reported for this variant.
PP1	Not met	No co-segregation data in affected family members is available for this variant.
PP2	Not met	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	Not met	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.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data is available to assess whether the clinical presentation is highly specific for TSC2-related disease.
PP5	Not met	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.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, well below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from population databases. Allele frequency is 0%, well below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available regarding observation of this variant in healthy adult individuals. The variant is absent from all population databases, precluding BS2 assessment.
BS3	Not met	No well-established functional studies demonstrating no damaging effect have been identified for this variant. OncoKB reports Unknown Oncogenic Effect for p.M327I.	oncokb
BS4	Not met	No family segregation data are available to assess lack of segregation with disease.
BP1	Not met	TSC2 is not a gene in which ONLY truncating variants cause disease. Pathogenic missense variants in TSC2 are well-established in tuberous sclerosis complex.
BP2	Not met	No data are available regarding observation of this variant in trans with a known pathogenic variant for tuberous sclerosis complex.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; not applicable to a missense substitution.
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not met	No data are available regarding observation of this variant in a case with an alternative molecular basis for disease.
BP6	Not met	This variant is absent from ClinVar and has not been reported as benign by any reputable source.	clinvar
BP7	Not met	This variant is a missense substitution (p.Met327Ile), not a synonymous variant. BP7 does not apply.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.