Submissions for variant NM_000548.5(TSC2):c.1839+6G>A

gnomAD frequency: 0.00046  dbSNP: rs45517204

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000233074	SCV000285258	benign	Tuberous sclerosis 2	2024-02-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000349195	SCV000342015	likely benign	not specified	2016-06-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000042920	SCV000395593	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV000349195	SCV000515024	benign	not specified	2015-03-13	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.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000513698	SCV000610731	likely benign	not provided	2017-05-11	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000233074	SCV000782400	uncertain significance	Tuberous sclerosis 2	2016-11-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000349195	SCV000918334	benign	not specified	2018-11-23	criteria provided, single submitter	clinical testing	Variant summary: TSC2 c.1839+6G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 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 0.00044 in 276158 control chromosomes, predominantly at a frequency of 0.0009 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex phenotype (6.9e-05), while the overall frequency of the variant is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant; these data strongly suggest that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1839+6G>A in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variants have been reported (TSC2 c.2968_2971dupAGGA, p.Ile991Lysfs*16; TSC2 c.2590C>T, p.Gln864*) (LOVD (Tuberous sclerosis database)), providing supporting evidence for a benign role. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign (4x) and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab	RCV000233074	SCV002039582	benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002255268	SCV002531008	benign	Hereditary cancer-predisposing syndrome	2021-01-28	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000513698	SCV002822236	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	TSC2: BP4, BS2
Ambry Genetics	RCV002255268	SCV003708736	likely benign	Hereditary cancer-predisposing syndrome	2021-10-27	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000513698	SCV004221407	benign	not provided	2020-02-19	criteria provided, single submitter	clinical testing
Tuberous sclerosis database (TSC2)	RCV000042920	SCV000066716	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
Clinical Genetics, Academic Medical Center	RCV000513698	SCV001921449	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000349195	SCV001970874	benign	not specified		no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000349195	SCV003839165	likely benign	not specified	2022-12-19	no assertion criteria provided	clinical testing