Submissions for variant NM_000548.5(TSC2):c.4536C>T (p.Asp1512=)

gnomAD frequency: 0.00288  dbSNP: rs35986575

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000118709	SCV000153124	benign	not specified	2021-06-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000118709	SCV000169154	benign	not specified	2013-10-11	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.
Ambry Genetics	RCV000163349	SCV000213883	likely benign	Hereditary cancer-predisposing syndrome	2014-10-14	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)	RCV000118709	SCV000229773	benign	not specified	2015-01-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206462	SCV000262450	benign	Tuberous sclerosis 2	2025-02-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000118709	SCV000305225	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000042764	SCV000395657	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001579476	SCV000605466	benign	not provided	2023-11-03	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000206462	SCV000677550	benign	Tuberous sclerosis 2	2017-05-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000118709	SCV000918328	benign	not specified	2018-01-02	criteria provided, single submitter	clinical testing	Variant summary: The TSC2 c.4536C>T (p.Asp1512Asp) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 852/276658 control chromosomes (3 homozygotes) at a frequency of 0.0030796, which is approximately 45 times the estimated maximal expected allele frequency of a pathogenic TSC2 variant (0.0000688), suggesting this variant is likely a benign polymorphism. This variant has been reported in multiple affected indiviudals without strong evidence for caulsality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign.
Genome-Nilou Lab	RCV000206462	SCV002039484	benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163349	SCV002533941	benign	Hereditary cancer-predisposing syndrome	2020-07-08	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV001579476	SCV002545719	likely benign	not provided	2024-11-01	criteria provided, single submitter	clinical testing	TSC2: BP4, BP7
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000206462	SCV004016088	benign	Tuberous sclerosis 2	2023-07-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000206462	SCV004360921	benign	Tuberous sclerosis 2	2019-03-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000042764	SCV004817500	benign	Tuberous sclerosis syndrome	2024-02-05	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001579476	SCV005217005	likely benign	not provided		criteria provided, single submitter	not provided
Tuberous sclerosis database (TSC2)	RCV000042764	SCV000066559	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
Tuberous sclerosis database (TSC2)	RCV000055290	SCV000083510	not provided	Lymphangiomyomatosis		no assertion provided	curation
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579476	SCV001807407	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000118709	SCV001922402	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001579476	SCV002033837	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001579476	SCV002036749	likely benign	not provided		no assertion criteria provided	clinical testing