ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.188C>T (p.Ala63Val) (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 RCV000161018 SCV000215136 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000161018 SCV000908800 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-30 criteria provided, single submitter clinical testing
Counsyl RCV000663264 SCV000786495 uncertain significance Li-Fraumeni syndrome 1 2018-05-14 criteria provided, single submitter clinical testing
GeneDx RCV000213047 SCV000211735 uncertain significance not provided 2017-11-02 criteria provided, single submitter clinical testing This variant is denoted TP53 c.188C>T at the cDNA level, p.Ala63Val (A63V) at the protein level, and results in the change of an Alanine to a Valine (GCT>GTT). This variant is reported as having functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Ala63Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. TP53 Ala63Val occurs at a position that is not conserved and is located in the SH3 Domain (Bode 2004). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether TP53 Ala63Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000467874 SCV000545312 uncertain significance Li-Fraumeni syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 63 of the TP53 protein (p.Ala63Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs372201428, ExAC 0.02%). This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 182922). An experimental study in yeast has shown that this variant does not impair the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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