Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP3_ModerateBS2
The NM_000548.5(TSC2):āc.736A>Gā(p.Thr246Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,459,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM1
?
PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 15 uncertain in NM_000548.5
PP3
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PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.908
BS2
?
BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
Uncertain significance, no assertion criteria provided
research
CSER _CC_NCGL, University of Washington
Jun 01, 2014
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not provided, no classification provided
curation
Tuberous sclerosis database (TSC2)
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Uncertain significance, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Dec 13, 2023
This missense variant replaces threonine with alanine at codon 246 of the TSC2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with tuberous sclerosis complex (PMID: 18772611). This variant has been identified in 4/249706 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Tuberous sclerosis 2 Benign:2
Likely benign, criteria provided, single submitter
clinical testing
Invitae
Jan 05, 2024
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Likely benign, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Nov 07, 2021
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not specified Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Sep 21, 2016
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr246Ala variant in TSC2 has been reported in 1 Asian individual as well as one family m ember with Tuberous Sclerosis (Sasongko 2008). This variant has been identified in 1/10372 African chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs137854123). Computational prediction tools and conservation analysis suggest that the p.Thr246Ala variant may impact the prote in, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Thr246Ala variant is uncertain. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Sep 30, 2022
Previously reported as a maternally inherited variant of uncertain significance in a patient suspected to have TSC; detailed clinical information not provided (Meng et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18466115, 26994145, 30564305, 18772611, 32917966, 25637381) -
Isolated focal cortical dysplasia type II Uncertain:1
Uncertain significance, criteria provided, single submitter
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Feb 12, 2024
The p.T246A variant (also known as c.736A>G), located in coding exon 7 of the TSC2 gene, results from an A to G substitution at nucleotide position 736. The threonine at codon 246 is replaced by alanine, an amino acid with similar properties. This alteration was detected in two members of a Japanese family with features of tuberous sclerosis (TSC) (Sasongko TH et al, 2008 May;54:E73-81). This alteration was identified in 1/374 Chinese patients with clinically suspected TSC undergoing genetic testing within the TSC1 and TSC2 genes, and was classified as a variant of unknown significance by the authors (Meng Y et al. J Hum Genet, 2021 Mar;66:227-236). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -