ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.188C>G (p.Ala63Gly) (rs372201428)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216082 SCV000272992 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000216082 SCV000908801 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587780 SCV000697433 uncertain significance not provided 2017-07-03 criteria provided, single submitter clinical testing Variant summary: The c.188C>G (p.Ala63Gly) in TP53 gene is a missense variant involves a non-conserved nucleotide and 3/5 in silico tools predict benign outcome. The variant is located within the mSin3a binding site, which is required for stabilization of p53 protein. In the functional study A63G was able to bind to mSin3a and thus prevent p53 from degradation. The variant is absent from control population datasets of ExAC and gnomAD. To our knowledge, the variant has not been reported in affected individuals via published reports, but is cited as VUS by reputable databases/clinical laboratories. Taken together, the variant was classified as VUS, until new information becomes available.
Invitae RCV000465288 SCV000545280 uncertain significance Li-Fraumeni syndrome 2018-05-30 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 63 of the TP53 protein (p.Ala63Gly). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and glycine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 229693). Experimental studies have shown that this missense change does not affect the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). In summary, this variant is a rare missense change that is not expected to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000614877 SCV000712636 uncertain significance not specified 2016-11-22 criteria provided, single submitter clinical testing The p.Ala63Gly variant in TP53 has not been previously reported as a germline va riant in individuals with Li-Fraumeni syndrome or in large population studies. C omputational prediction tools and conservation analysis suggest that the variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ala63Gly variant is uncertain.

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