ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.1915C>T (p.Arg639Trp)

gnomAD frequency: 0.00003  dbSNP: rs766451267
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001705070 SCV000243662 likely benign not provided 2020-10-19 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 28687356, 32555378)
Labcorp Genetics (formerly Invitae), Labcorp RCV000557012 SCV000644295 likely benign Tuberous sclerosis 2 2025-01-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000570781 SCV000664664 likely benign Hereditary cancer-predisposing syndrome 2022-03-31 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001705070 SCV001474095 uncertain significance not provided 2020-03-19 criteria provided, single submitter clinical testing The TSC2 c.1915C>T; p.Arg639Trp variant (rs766451267) is reported in the literature in an individual with malignant pleural mesothelioma and a family history of breast cancer, but this individual also carried a variant of uncertain significance in FANCA (Betti 2017). The p.Arg639Trp variant is reported in the ClinVar database (Variation ID: 207723). It is found in the general population with an overall allele frequency of 0.004% (10/250400 alleles) in the Genome Aggregation Database. The arginine at codon 639 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Betti M et al. Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma. Cancer Lett. 2017 Oct 1;405:38-45.
Genome-Nilou Lab RCV000557012 SCV002039590 likely benign Tuberous sclerosis 2 2021-11-07 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000570781 SCV002531014 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-07 criteria provided, single submitter curation
CeGaT Center for Human Genetics Tuebingen RCV001705070 SCV002822237 likely benign not provided 2022-12-01 criteria provided, single submitter clinical testing TSC2: BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003155114 SCV003844771 likely benign not specified 2023-02-15 criteria provided, single submitter clinical testing Variant summary: TSC2 c.1915C>T (p.Arg639Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 250400 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex (4e-05 vs 6.9e-05), allowing no conclusion about variant significance. c.1915C>T has been reported in the literature in individuals affected with Tuberous Sclerosis Complex. These reports do not provide unequivocal conclusions about association of the variant with Tuberous Sclerosis Complex. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Rosengren_2020). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign n=5, VUS n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV003155114 SCV004221409 benign not specified 2022-10-10 criteria provided, single submitter clinical testing The frequency of this variant in the general population (http://gnomad.broadinstitute.org) is higher than would generally be expected for pathogenic variants in this gene. This variant has been seen where an alternate explanation for disease was also identified. Assessment of experimental evidence regarding the effect of this variant on protein function suggests it has no effect relevant to disease (PMID:PMID 32555378).
All of Us Research Program, National Institutes of Health RCV003996886 SCV004814948 likely benign Tuberous sclerosis syndrome 2024-08-13 criteria provided, single submitter clinical testing

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