ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.5252G>A (p.Arg1751His)

gnomAD frequency: 0.00002  dbSNP: rs373365980
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000190042 SCV000243716 uncertain significance not provided 2017-10-26 criteria provided, single submitter clinical testing This variant is denoted TSC2 c.5252G>A at the cDNA level, p.Arg1751His (R1751H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. TSC2 Arg1751His was observed at an allele frequency of 0.01% (1/10,068 alleles) in large population cohorts (Lek 2016). This variant is located in the Rap-GAP domain (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether TSC2 Arg1751His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV001084515 SCV000544472 benign Tuberous sclerosis 2 2024-01-17 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001084515 SCV002040266 likely benign Tuberous sclerosis 2 2021-11-07 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV002257483 SCV002534039 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-26 criteria provided, single submitter curation
Ambry Genetics RCV002257483 SCV002643810 likely benign Hereditary cancer-predisposing syndrome 2021-09-10 criteria provided, single submitter clinical testing This alteration is classified as likely 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.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University RCV003153466 SCV003843663 likely pathogenic Ovarian cancer 2022-01-01 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003895237 SCV004710604 uncertain significance TSC2-related condition 2024-02-12 criteria provided, single submitter clinical testing The TSC2 c.5252G>A variant is predicted to result in the amino acid substitution p.Arg1751His. This variant was reported in an individual with breast cancer (Table S2, McDonald et al. 2022. PubMed ID: 36315513). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from benign to likely pathogenic (http://www.ncbi.nlm.nih.gov/clinvar/variation/207760). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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