ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.5094C>A (p.Ser1698Arg) (rs45514196)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000122241 SCV000169161 benign not specified 2013-09-11 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000122241 SCV000230503 likely benign not specified 2015-02-12 criteria provided, single submitter clinical testing
Invitae RCV000226602 SCV000285439 benign Tuberous sclerosis 2 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000042711 SCV000395673 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.
Ambry Genetics RCV000569332 SCV000675477 likely benign Hereditary cancer-predisposing syndrome 2019-01-24 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification;Other data supporting benign classification
Tuberous sclerosis database (TSC2) RCV000042711 SCV000066506 not provided Tuberous sclerosis syndrome no assertion provided curation
ITMI RCV000122241 SCV000086464 not provided not specified 2013-09-19 no assertion provided reference population
Broad Institute Rare Disease Group,Broad Institute RCV000122241 SCV001423029 likely benign not specified 2020-01-22 no assertion criteria provided curation The p.Ser1698Arg variant in TSC2 has been reported in at least 2 individuals with tuberous sclerosis complex (PMID: 17304050), but has also been identified in at least 2 individuals from a healthy cohort (PMID: 24728327) and 0.3421% (85/24850) of African chromosomes, 0.01129% (4/35420) of Latino chromosomes, and 0.0007790% (1/128370) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs45514196). This variant has been reported benign and likely benign in ClinVar (Variation ID: 49451). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. One additional variant, resulting in a different amino acid change at the same position, p.Ser1698Thr, has been reported as a VUS in association with disease in ClinVar (Variation ID: 578397). At least 2 unaffected individuals with the variant have been reported in the literature (PMID: 24728327) and tuberous sclerosis complex is fully penetrant except in rare cases with mild mutations (PMID: 27226234), slightly increasing the likelihood that this variant is benign. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BS2_Supporting (Richards 2015).

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