Submissions for variant NM_000548.5(TSC2):c.5094C>A (p.Ser1698Arg)

dbSNP: rs45514196

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000122241	SCV000169161	benign	not specified	2013-09-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Eurofins Ntd Llc (ga)	RCV000122241	SCV000230503	likely benign	not specified	2015-02-12	criteria provided, single submitter	clinical testing
Invitae	RCV000226602	SCV000285439	benign	Tuberous sclerosis 2	2024-01-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000042711	SCV000395673	benign	Tuberous sclerosis syndrome	2018-01-13	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Ambry Genetics	RCV000569332	SCV000675477	likely benign	Hereditary cancer-predisposing syndrome	2019-01-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000122241	SCV001423029	likely benign	not specified	2020-01-22	criteria provided, single submitter	curation	The p.Ser1698Arg variant in TSC2 has been reported in at least 2 individuals with tuberous sclerosis complex (PMID: 17304050), but has also been identified in at least 2 individuals from a healthy cohort (PMID: 24728327) and 0.3421% (85/24850) of African chromosomes, 0.01129% (4/35420) of Latino chromosomes, and 0.0007790% (1/128370) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs45514196). This variant has been reported benign and likely benign in ClinVar (Variation ID: 49451). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. One additional variant, resulting in a different amino acid change at the same position, p.Ser1698Thr, has been reported as a VUS in association with disease in ClinVar (Variation ID: 578397). At least 2 unaffected individuals with the variant have been reported in the literature (PMID: 24728327) and tuberous sclerosis complex is fully penetrant except in rare cases with mild mutations (PMID: 27226234), slightly increasing the likelihood that this variant is benign. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BS2_Supporting (Richards 2015).
Athena Diagnostics Inc	RCV000122241	SCV001476304	benign	not specified	2020-08-13	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000226602	SCV002039903	benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000569332	SCV002534013	benign	Hereditary cancer-predisposing syndrome	2021-04-05	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000226602	SCV004016206	benign	Tuberous sclerosis 2	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003390734	SCV004129879	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	TSC2: BS1
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003390734	SCV004221466	benign	not provided	2020-08-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003390734	SCV004562106	likely benign	not provided	2023-06-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003944957	SCV004761567	likely benign	TSC2-related condition	2019-12-16	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)	RCV000042711	SCV000066506	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
ITMI	RCV000122241	SCV000086464	not provided	not specified	2013-09-19	no assertion provided	reference population