Submissions for variant NM_000548.5(TSC2):c.560A>G (p.Asn187Ser)

gnomAD frequency: 0.00001  dbSNP: rs45505405

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163373	SCV000213912	likely benign	Hereditary cancer-predisposing syndrome	2022-06-17	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.
GeneDx	RCV000190050	SCV000243725	uncertain significance	not provided	2018-11-20	criteria provided, single submitter	clinical testing	This variant is denoted TSC2 c.560A>G at the cDNA level, p.Asn187Ser (N187S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. TSC2 Asn187Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the TSC1 binding domain (Huang 2008). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether TSC2 Asn187Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086110	SCV000285464	likely benign	Tuberous sclerosis 2	2024-10-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765260	SCV000896513	uncertain significance	Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2	2018-10-31	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001086110	SCV002041074	uncertain significance	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995252	SCV004816975	uncertain significance	Tuberous sclerosis syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 187 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 5/251496 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.
Athena Diagnostics	RCV000190050	SCV005621390	uncertain significance	not provided	2024-01-19	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) This variant has been seen where an alternate explanation for disease was also identified, suggesting this variant may not cause disease. Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000190050	SCV005622739	uncertain significance	not provided	2024-10-22	criteria provided, single submitter	clinical testing	The TSC2 c.560A>G (p.Asn187Ser) variant has not been reported in individuals with TSC2-related conditions in the published literature. However, the variant has been observed in a cohort of individuals with T-cell acute lymphoblastic leukemia (PMID: 31721781 (2019)). The frequency of this variant in the general population, 0.000035 (4/113770 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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. Based on the available information, we are unable to determine the clinical significance of this variant.