Submissions for variant NM_000548.5(TSC2):c.1808C>G (p.Thr603Ser)

dbSNP: rs1318655892

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001932092	SCV002123892	uncertain significance	Tuberous sclerosis 2	2024-07-08	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 603 of the TSC2 protein (p.Thr603Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of tuberous sclerosis complex (PMID: 31856217). ClinVar contains an entry for this variant (Variation ID: 1362039). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002406943	SCV002713209	likely benign	Hereditary cancer-predisposing syndrome	2022-10-17	criteria provided, single submitter	clinical testing	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.
All of Us Research Program, National Institutes of Health	RCV004804262	SCV005427106	uncertain significance	Tuberous sclerosis syndrome	2024-06-17	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 603 of the TSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with lymphangioleiomyomatosis (PMID:31856217). This variant has not been identified 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001932092	SCV005689350	uncertain significance	Tuberous sclerosis 2	2024-08-24	criteria provided, single submitter	clinical testing	The TSC2 c.1808C>G (p.Thr603Ser) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in an individual with lymphangioleiomyomatosis (LAM) (PMID: 31856217). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.