Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM5BP6BS2
The NM_000548.5(TSC2):c.4639G>A(p.Val1547Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,612,608 control chromosomes in the GnomAD database, including 1 homozygotes. 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. V1547G) has been classified as Pathogenic.
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 -1 ACMG points.
PM1
In a domain Rap-GAP (size 227) in uniprot entity TSC2_HUMAN there are 284 pathogenic changes around while only 47 benign (86%) in NM_000548.5
PM5
Other missense variant is known to change same aminoacid residue: Variant chr16-2085300-T-G is described in Lovd as [Pathogenic].
BP6
Variant 16-2085299-G-A is Benign according to our data. Variant chr16-2085299-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 238056.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=1}.
Likely benign, criteria provided, single submitter
clinical testing
Myriad Genetics, Inc.
Aug 23, 2024
This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Likely benign, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Nov 07, 2021
- -
Likely benign, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Jan 27, 2024
- -
Isolated focal cortical dysplasia type II Pathogenic:1
Pathogenic, no assertion criteria provided
literature only
OMIM
Apr 11, 2017
- -
Tuberous sclerosis syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
May 09, 2024
This missense variant replaces valine with isoleucine at codon 1547 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 TSC2-related disorders in the literature. This variant has been identified in 7/249908 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. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Dec 12, 2022
Identified as a somatic variant in the brain of a patient with focal cortical dysplasia type IIa; this patient did not have any features of TSC (Lim et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously reported as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 28215400, 18466115) -
TSC2-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided
clinical testing
PreventionGenetics, part of Exact Sciences
Aug 16, 2024
The TSC2 c.4639G>A variant is predicted to result in the amino acid substitution p.Val1547Ile. This variant was identified as a somatic variant in the brain of a patient with focal cortical dysplasia type IIa (Lim et al 2017. PubMed ID: 28215400). This variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD. This variant has interpretations ranging from benign to pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/238056/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Jan 19, 2021
This alteration is classified as 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. -