ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.275A>T (p.Glu92Val)

gnomAD frequency: 0.00101  dbSNP: rs137853994
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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130758 SCV000185649 benign Hereditary cancer-predisposing syndrome 2018-12-18 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 RCV001703939 SCV000243626 benign not provided 2019-03-19 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 21407264, 23514105, 22558107, 21624971, 24728327, 28873162, 29801666)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000122217 SCV000270956 likely benign not specified 2020-07-01 criteria provided, single submitter clinical testing The c.275A>T variant in TSC2 has been reported in individuals with Tuberous Sclerosis Complex (Dunlop 2011 PMID: 21407264, Bullich 2018 PMID: 29801666); however, it has also been identified in 0.17% (189/109664) of Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 50116). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant is classified as Likely Benign due to its frequency in the general population. ACMG/AMP Criteria applied: BS1, BP4.
Invitae RCV000989412 SCV000285313 benign Tuberous sclerosis 2 2024-02-01 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV000122217 SCV000305186 likely benign not specified criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000043383 SCV000395556 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.
Eurofins Ntd Llc (ga) RCV000122217 SCV000703518 benign not specified 2016-12-27 criteria provided, single submitter clinical testing
Mendelics RCV000989412 SCV001139734 likely benign Tuberous sclerosis 2 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000122217 SCV001338115 likely benign not specified 2020-01-27 criteria provided, single submitter clinical testing Variant summary: TSC2 c.275A>T (p.Glu92Val) results in a non-conservative amino acid change located in the N-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 213250 control chromosomes (gnomAD). The observed variant frequency is approximately 14.6- fold the estimated maximal expected allele frequency for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex phenotype (6.9e-05), strongly suggesting that the variant is benign. c.275A>T has been reported in the literature in individuals affected with Tuberous Sclerosis Complex (examples-Dunlop_2011, Bullich_2018) and in at least one unaffected family member (Dunlop_2011). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Dunlop_2011). Seven ClinVar submitters (evaluation after 2014) classified the variant as benign (n=2)/likely benign (n=5). Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001703939 SCV001477594 likely benign not provided 2023-11-07 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000989412 SCV002041202 benign Tuberous sclerosis 2 2021-11-07 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000130758 SCV002533326 benign Hereditary cancer-predisposing syndrome 2020-09-21 criteria provided, single submitter curation
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001703939 SCV002774072 benign not provided 2019-03-14 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002477140 SCV002801178 likely benign Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2 2022-04-09 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001703939 SCV003917448 benign not provided 2023-09-01 criteria provided, single submitter clinical testing TSC2: BP4, BS1, BS2
KCCC/NGS Laboratory, Kuwait Cancer Control Center RCV000989412 SCV004016162 benign Tuberous sclerosis 2 2023-07-07 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000989412 SCV004360844 benign Tuberous sclerosis 2 2022-08-10 criteria provided, single submitter clinical testing
Tuberous sclerosis database (TSC2) RCV000043383 SCV000067189 not provided Tuberous sclerosis syndrome no assertion provided curation
ITMI RCV000122217 SCV000086438 not provided not specified 2013-09-19 no assertion provided reference population

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