Submissions for variant NM_000548.5(TSC2):c.1577G>C (p.Ser526Thr)

gnomAD frequency: 0.00010  dbSNP: rs376573446

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001200210	SCV000243545	likely benign	not provided	2020-09-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000557687	SCV000644258	benign	Tuberous sclerosis 2	2025-01-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000564968	SCV000675568	likely benign	Hereditary cancer-predisposing syndrome	2018-12-06	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)	RCV000189889	SCV000859707	likely benign	not specified	2018-03-02	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768351	SCV000899049	uncertain significance	Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2	2021-03-30	criteria provided, single submitter	clinical testing	TSC2 NM_000548 exon 15 p.Ser526Thr (c.1577G>C): This variant has not been reported in the literature but is present in 15/126622 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs376573446). This variant is present in ClinVar (Variation ID:207659). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
CeGaT Center for Human Genetics Tuebingen	RCV001200210	SCV001371110	likely benign	not provided	2020-04-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000557687	SCV002039554	likely benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000564968	SCV002530970	likely benign	Hereditary cancer-predisposing syndrome	2021-04-15	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000189889	SCV005423591	likely benign	not specified	2024-10-01	criteria provided, single submitter	clinical testing	Variant summary: TSC2 c.1577G>C (p.Ser526Thr) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251166 control chromosomes, predominantly at a frequency of 0.00011 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 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex phenotype (6.9e-05). To our knowledge, no occurrence of c.1577G>C in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 207659). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001200210	SCV005625982	uncertain significance	not provided	2024-01-11	criteria provided, single submitter	clinical testing