ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.66A>G (p.Leu22=) (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: 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.
Invitae RCV000196762 SCV000254635 likely benign Li-Fraumeni syndrome 2020-12-02 criteria provided, single submitter clinical testing
GeneDx RCV000483133 SCV000565620 uncertain significance not provided 2018-05-24 criteria provided, single submitter clinical testing This variant is denoted TP53 c.66A>G at the DNA level. This variant is silent at the coding level, preserving a Leucine at codon 22. Although this variant is not predicted to affect splicing, it is located at a position that potentially impacts the tertiary structure of p53 mRNA (F?hraeus 2015). This variant was observed in various assays to reduce several functions including p53-induced apoptosis, p53 mRNA binding to MDM2, in vitro transcription and internal ribosome entry site activity (Candeias 2008, Grover 2011, Malbert-Colas 2014). TP53 c.66A>G was not observed at a significant allele frequency in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether TP53 c.66A>G is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000163369 SCV000686760 uncertain significance Hereditary cancer-predisposing syndrome 2021-02-17 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.
Mendelics RCV000196762 SCV000839128 uncertain significance Li-Fraumeni syndrome 2018-07-02 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

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