Submissions for variant NM_000548.5(TSC2):c.2580T>C (p.Phe860=)

gnomAD frequency: 0.08017  dbSNP: rs13337626

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163258	SCV000213786	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as 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)	RCV000118702	SCV000228020	benign	not specified	2014-10-16	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000118702	SCV000269918	benign	not specified	2013-02-21	criteria provided, single submitter	clinical testing	Phe860Phe in exon 23 of TSC2: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 8.7% (381/4396) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs13337626).
PreventionGenetics, part of Exact Sciences	RCV000118702	SCV000305182	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000042833	SCV000395615	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	RCV000576366	SCV000677541	benign	Tuberous sclerosis 2	2017-04-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587006	SCV000697464	benign	not provided	2016-08-23	criteria provided, single submitter	clinical testing	Variant summary: The TSC2 c.2580T>C (p.Phe860Phe) variant causes a synonymous change involving a non-conserved nucleotide with 4/5 splice prediction tools predicting no significant impact on splicing and alterations to ESE binding, however, these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 8679/119772 (1/13, 390 homozygotes), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic TSC2 variant of 1/14534, suggesting this variant is likely a benign polymorphism. In addition, multiple reputable clinical laboratories/databases cite the variant as "likely benign/benign." Therefore, the variant of interest has been classified as Benign.
Invitae	RCV000576366	SCV001723413	benign	Tuberous sclerosis 2	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000587006	SCV001758342	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000576366	SCV002039218	benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587006	SCV002048136	benign	not provided	2023-11-30	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000576366	SCV004016098	benign	Tuberous sclerosis 2	2023-07-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000576366	SCV004360884	benign	Tuberous sclerosis 2	2019-03-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000042833	SCV004817470	benign	Tuberous sclerosis syndrome	2024-02-05	criteria provided, single submitter	clinical testing
Tuberous sclerosis database (TSC2)	RCV000042833	SCV000066629	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
Tuberous sclerosis database (TSC2)	RCV000055364	SCV000083585	not provided	Lymphangiomyomatosis		no assertion provided	curation
Genetic Services Laboratory, University of Chicago	RCV000118702	SCV000153117	likely benign	not specified		no assertion criteria provided	clinical testing	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.
Clinical Genetics, Academic Medical Center	RCV000118702	SCV001926088	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000118702	SCV001973192	benign	not specified		no assertion criteria provided	clinical testing