NM_000548.5:c.5186G>A

TSC2 · NP_000539.2:p.(Arg1729His) · NM_000548.5

GRCh37: chr16:2138253 G>A · GRCh38: chr16:2088252 G>A

Gene: TSC2 Transcript: NM_000548.5

Final call

VUS

PM2 supporting BP6 supporting benign

Variant details

Gene

TSC2

Transcript

NM_000548.5

Protein

NP_000539.2:p.(Arg1729His)

gnomAD AF

3.5522694639438414e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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	N/A	NM_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.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No same-amino-acid change comparator variant with established pathogenicity was identified for p.Arg1729His. Insufficient data to assess PS1.
PS2	Not assessed	No de novo observation data were identified for NM_000548.5:c.5186G>A in any reviewed source.
PS3	Not met	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.	oncokb
PS4	Not assessed	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.
PS5	Not met	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.	clinvar
PM1	Not assessed	Residue p.Arg1729 does not lie within a statistically significant cancer hotspot. No domain-level functional evidence was curated for PM1 assessment.
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	N/A	No 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.	pm5_candidates
PM6	Not assessed	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.
PP1	Not assessed	No cosegregation data were identified for NM_000548.5:c.5186G>A in any reviewed source.
PP2	Not assessed	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history data were available for NM_000548.5:c.5186G>A to assess specificity for tuberous sclerosis complex.
PP5	Not met	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.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not met	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.	gnomad_v2 gnomad_v4
BS3	Not met	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.	oncokb
BS4	Not assessed	No cosegregation data were available to assess lack of segregation with disease for NM_000548.5:c.5186G>A.
BP1	Not assessed	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.
BP2	Not assessed	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.
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not assessed	No data were available on whether NM_000548.5:c.5186G>A was observed in a case with an alternative molecular basis for disease.
BP6	Met	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.	clinvar
BP7	N/A	NM_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.

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