Submissions for variant NM_000548.5(TSC2):c.2743-3C>A

gnomAD frequency: 0.00033  dbSNP: rs45517264

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129609	SCV000184396	likely benign	Hereditary cancer-predisposing syndrome	2018-09-20	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	RCV001703931	SCV000243571	benign	not provided	2020-09-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471545	SCV000556567	benign	Tuberous sclerosis 2	2024-01-31	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000471545	SCV002039246	benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129609	SCV002533321	likely benign	Hereditary cancer-predisposing syndrome	2021-05-31	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV001703931	SCV004133837	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	TSC2: BP4, BS2
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003488360	SCV004221422	likely benign	not specified	2024-04-04	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population (http://gnomad.broadinstitute.org) is higher than would generally be expected for pathogenic variants in this gene. Computational tools yielded predictions that this variant may interfere with normal RNA splicing. This variant has been seen where an alternate explanation for disease was also identified.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488360	SCV004241657	benign	not specified	2023-12-26	criteria provided, single submitter	clinical testing	Variant summary: TSC2 c.2743-3C>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a canonical 3' acceptor site. One predict the variant abolishes a canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00027 in 250692 control chromosomes, predominantly at a frequency of 0.00056 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 8 fold of 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.2743-3C>A in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000471545	SCV004360887	likely benign	Tuberous sclerosis 2	2022-09-20	criteria provided, single submitter	clinical testing
Tuberous sclerosis database (TSC2)	RCV000042488	SCV000066279	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
PreventionGenetics, part of Exact Sciences	RCV004537160	SCV004741895	likely benign	TSC2-related disorder	2023-09-08	no assertion criteria provided	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).