Submissions for variant NM_000548.5(TSC2):c.3770C>T (p.Ala1257Val)

gnomAD frequency: 0.00022  dbSNP: rs45466493

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163870	SCV000214457	benign	Hereditary cancer-predisposing syndrome	2015-06-30	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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	RCV000189919	SCV000243582	likely benign	not specified	2018-02-06	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.
Invitae	RCV001082168	SCV000285365	benign	Tuberous sclerosis 2	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000054860	SCV001277608	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV000034651	SCV001334514	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	TSC2: BS2
Genome-Nilou Lab	RCV001082168	SCV002039372	benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163870	SCV002533451	benign	Hereditary cancer-predisposing syndrome	2020-05-27	criteria provided, single submitter	curation
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003227624	SCV003924170	likely benign	Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2	2021-03-30	criteria provided, single submitter	clinical testing	TSC2 NM_000548.4 exon 31 p.Ala1257Val (c.3770C>T): This variant has not been reported in the literature but is present in 0.01% (7/64568) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-2081754-C-T?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as benign or likely benign (Variation ID:41734). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001082168	SCV004016187	benign	Tuberous sclerosis 2	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001082168	SCV004018703	benign	Tuberous sclerosis 2	2023-07-06	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034651	SCV004221444	likely benign	not provided	2016-07-06	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034651	SCV000043534	probably not pathogenic	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Likely benign.
Tuberous sclerosis database (TSC2)	RCV000054860	SCV000066832	not provided	Tuberous sclerosis syndrome		no assertion provided	curation