Submissions for variant NM_000548.5(TSC2):c.2220+4C>G

gnomAD frequency: 0.00005  dbSNP: rs781186613

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000727502	SCV000521318	uncertain significance	not provided	2023-11-29	criteria provided, single submitter	clinical testing	In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV000574046	SCV000675475	likely benign	Hereditary cancer-predisposing syndrome	2022-04-04	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.
Eurofins Ntd Llc (ga)	RCV000727502	SCV000709197	uncertain significance	not provided	2017-06-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079788	SCV000765859	likely benign	Tuberous sclerosis 2	2025-01-20	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001079788	SCV002039627	uncertain significance	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000574046	SCV002531043	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-27	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV004000345	SCV004822237	uncertain significance	Tuberous sclerosis syndrome	2024-06-11	criteria provided, single submitter	clinical testing	This variant causes a C to G nucleotide substitution at the +4 position of intron 20 of the TSC2 gene. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TSC2-related disorders in the literature. This variant has been identified in 2/250742 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.
Myriad Genetics, Inc.	RCV001079788	SCV005404766	likely benign	Tuberous sclerosis 2	2024-08-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000727502	SCV005622746	uncertain significance	not provided	2023-12-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004539808	SCV004799965	uncertain significance	TSC2-related disorder	2024-01-19	no assertion criteria provided	clinical testing	The TSC2 c.2220+4C>G variant is predicted to interfere with splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. In ClinVar, this variant is interpreted as uncertain/likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/381732/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.