Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS2
The NM_000548.5(TSC2):āc.3140T>Cā(p.Val1047Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000283 in 1,612,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1047M) has been classified as Benign.
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 Likely_benign. Variant got -5 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 14 uncertain in NM_000548.5
BP4
Computational evidence support a benign effect (MetaRNN=0.16717708).
BP6
Variant 16-2079284-T-C is Benign according to our data. Variant chr16-2079284-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 49565.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, not_provided=2, Benign=1, Uncertain_significance=3}. Variant chr16-2079284-T-C is described in Lovd as [Benign].
Likely benign, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Aug 05, 2021
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Uncertain significance, criteria provided, single submitter
clinical testing
Eurofins Ntd Llc (ga)
Apr 14, 2017
- -
Uncertain significance, criteria provided, single submitter
clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Nov 03, 2021
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Tuberous sclerosis syndrome Uncertain:1Other:1
not provided, no classification provided
curation
Tuberous sclerosis database (TSC2)
-
- -
Uncertain significance, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Dec 14, 2023
This missense variant replaces valine with alanine at codon 1047 of the TSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with tuberous sclerosis complex in the literature. This variant has been identified in 37/281746 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
Benign, criteria provided, single submitter
clinical testing
Invitae
Jan 30, 2024
- -
Likely benign, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Nov 07, 2021
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Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Sep 14, 2018
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter
curation
Sema4, Sema4
Jan 20, 2021
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not specified Benign:1Other:1
Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Jan 08, 2018
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
not provided, no classification provided
reference population
ITMI
Sep 19, 2013
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TSC2-related disorder Benign:1
Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Aug 24, 2023
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -