Submissions for variant NM_000548.5(TSC2):c.4136C>T (p.Ser1379Leu)

gnomAD frequency: 0.00007  dbSNP: rs137854065

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000731274	SCV000243753	likely benign	not provided	2020-09-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22903760, 23514105)
Invitae	RCV001083321	SCV000544540	benign	Tuberous sclerosis 2	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000575789	SCV000664656	benign	Hereditary cancer-predisposing syndrome	2021-01-27	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Eurofins Ntd Llc (ga)	RCV000731274	SCV000859070	uncertain significance	not provided	2018-01-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001083321	SCV002039830	likely benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000575789	SCV002533505	likely benign	Hereditary cancer-predisposing syndrome	2020-11-11	criteria provided, single submitter	curation
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	RCV001083321	SCV002559809	uncertain significance	Tuberous sclerosis 2	2022-08-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000731274	SCV004221455	uncertain significance	not provided	2015-11-27	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported as a somatic variant in refractory multiple myeloma (PMID: 35768438 (2022)) and supratentorial ependymoma (PMID: 31375768 (2020)). Additionally, this variant has been reported in an individual suspected of tuberous sclerosis (PMID: 22903760 (2012)). The frequency of this variant in the general population, 0.00012 (8/68026 chromosomes in European (non-Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on TSC2 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, we are unable to determine the clinical significance of this variant.
PreventionGenetics, part of Exact Sciences	RCV003905020	SCV004732961	likely benign	TSC2-related condition	2021-08-25	criteria provided, single submitter	clinical testing	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).
Tuberous sclerosis database (TSC2)	RCV000055582	SCV000083806	not provided	Tuberous sclerosis syndrome		no assertion provided	curation