ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.4346C>T (p.Ser1449Phe)

gnomAD frequency: 0.00003  dbSNP: rs759004251
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000232439 SCV000285398 likely benign Tuberous sclerosis 2 2025-01-30 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000502912 SCV000597597 uncertain significance not specified 2017-03-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000562405 SCV000664705 likely benign Hereditary cancer-predisposing syndrome 2022-10-18 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.
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000232439 SCV000782410 uncertain significance Tuberous sclerosis 2 2016-11-01 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000232439 SCV002039850 uncertain significance Tuberous sclerosis 2 2021-11-07 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004532852 SCV004113451 uncertain significance TSC2-related disorder 2022-12-19 criteria provided, single submitter clinical testing The TSC2 c.4346C>T variant is predicted to result in the amino acid substitution p.Ser1449Phe. This variant was reported in a patient with breast cancer (Table S2, Chan et al. 2018. PubMed ID: 30093976). This variant is reported in 0.00080% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-2134569-C-T). In ClinVar this variant is interpreted by other laboratories as uncertain (3) and likely benign (2) (https://www.ncbi.nlm.nih.gov/clinvar/variation/238045/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health RCV003998827 SCV004827052 uncertain significance Tuberous sclerosis syndrome 2023-06-26 criteria provided, single submitter clinical testing This missense variant replaces serine with phenylalanine at codon 1449 of the TSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with tuberous sclerosis complex in the literature. This variant has been identified in 1/271192 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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