ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.66A>G (p.Leu22=)

dbSNP: rs748527030
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163369 SCV000213908 likely benign Hereditary cancer-predisposing syndrome 2014-08-08 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000196762 SCV000254635 likely benign Li-Fraumeni syndrome 2024-01-10 criteria provided, single submitter clinical testing
GeneDx RCV000483133 SCV000565620 uncertain significance not provided 2022-10-20 criteria provided, single submitter clinical testing Nucleotide substitution has no predicted effect on splicing and is not conserved across species; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23027126, 21317560, 26513723, 19160491, 24813712, 22264786, 21722702, 24343861, 26657150, 27776193, 24665023, 30252118, 31519161)
Color Diagnostics, LLC DBA Color Health RCV000163369 SCV000686760 likely benign Hereditary cancer-predisposing syndrome 2022-10-28 criteria provided, single submitter clinical testing
Mendelics RCV000989728 SCV001140271 uncertain significance Squamous cell carcinoma of the head and neck 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001174848 SCV001338233 likely benign not specified 2020-02-29 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000196762 SCV004823861 likely benign Li-Fraumeni syndrome 2023-02-24 criteria provided, single submitter clinical testing This variant is a single nucleotide change located in the IRES translation signal of the TP53 mRNA. The variant is a synonymous change at the protein level. Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have demonstrated that this variant reduces the interaction of MDM2 with the TP53 mRNA IRES hairpin. This has been shown to decrease translation efficiency, phosphorylation of the nascent TP53 protein by ATM, and the stabilization of p53 following genotoxic stress (PMID: 19160491, 21317560, 22264786, 24813712, 26513723, 30252118, 30828720). This variant has been reported in an individual affected with chronic lymphocyte leukemia in the literature (PMID: 12149195). This variant has been identified in 1/250396 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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