Submissions for variant NM_000548.5(TSC2):c.2372G>T (p.Cys791Phe)

gnomAD frequency: 0.00001  dbSNP: rs758961134

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000307485	SCV000395610	uncertain significance	Tuberous sclerosis syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000687605	SCV000815182	benign	Tuberous sclerosis 2	2023-06-16	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000687605	SCV002040699	uncertain significance	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002450875	SCV002735883	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-28	criteria provided, single submitter	clinical testing	The p.C791F variant (also known as c.2372G>T), located in coding exon 21 of the TSC2 gene, results from a G to T substitution at nucleotide position 2372. The cysteine at codon 791 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002487404	SCV002775307	uncertain significance	Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2	2022-02-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003469253	SCV004205119	likely benign	Isolated focal cortical dysplasia type II	2022-05-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000307485	SCV004829813	uncertain significance	Tuberous sclerosis syndrome	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with phenylalanine at codon 791 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 not been reported in individuals affected with tuberous sclerosis complex in the literature. This variant has been identified in 1/249336 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.
PreventionGenetics, part of Exact Sciences	RCV004734976	SCV005362489	uncertain significance	TSC2-related disorder	2024-09-05	no assertion criteria provided	clinical testing	The TSC2 c.2372G>T variant is predicted to result in the amino acid substitution p.Cys791Phe. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.