Submissions for variant NM_000548.5(TSC2):c.255C>T (p.Val85=)

gnomAD frequency: 0.00077  dbSNP: rs45517098

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000125703	SCV000169168	benign	not specified	2013-04-01	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.
Ambry Genetics	RCV000163465	SCV000214016	likely benign	Hereditary cancer-predisposing syndrome	2014-10-07	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.
Invitae	RCV000203895	SCV000262488	benign	Tuberous sclerosis 2	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000125703	SCV000305180	benign	not specified		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000125703	SCV000339339	benign	not specified	2016-02-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000042832	SCV000395553	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.
Athena Diagnostics Inc	RCV000203895	SCV000677540	benign	Tuberous sclerosis 2	2017-05-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000125703	SCV000920330	benign	not specified	2018-10-08	criteria provided, single submitter	clinical testing	Variant summary: TSC2 c.255C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0011 in 235020 control chromosomes (gnomAD). The observed variant frequency is approximately 16-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex phenotype (6.9e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.255C>T in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000125703	SCV001365846	likely benign	not specified	2013-02-21	criteria provided, single submitter	clinical testing	Val85Val in exon 4 of TSC2: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0.2% (16/8582) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs45517098).
CeGaT Center for Human Genetics Tuebingen	RCV001531835	SCV001747133	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	TSC2: BP4, BP7, BS1
Genome-Nilou Lab	RCV000203895	SCV002041194	benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163465	SCV002531085	benign	Hereditary cancer-predisposing syndrome	2020-10-30	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000125703	SCV002774070	benign	not specified	2021-08-14	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000203895	SCV004016180	benign	Tuberous sclerosis 2	2023-07-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000203895	SCV004360842	benign	Tuberous sclerosis 2	2022-09-16	criteria provided, single submitter	clinical testing
Tuberous sclerosis database (TSC2)	RCV000042832	SCV000066628	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
Clinical Genetics, Academic Medical Center	RCV001531835	SCV001919083	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000125703	SCV001965763	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001531835	SCV002036557	likely benign	not provided		no assertion criteria provided	clinical testing