ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.256G>A (p.Ala86Thr) (rs587782148)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130712 SCV000185599 likely benign Hereditary cancer-predisposing syndrome 2018-01-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Intact protein function observed in appropriate functional assay(s),In silico models in agreement (benign)
Color RCV000130712 SCV000911118 benign Hereditary cancer-predisposing syndrome 2016-11-28 criteria provided, single submitter clinical testing
GeneDx RCV000478688 SCV000571555 uncertain significance not provided 2016-09-01 criteria provided, single submitter clinical testing This variant is denoted TP53 c.256G>A at the cDNA level, p.Ala86Thr (A86T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). This variant has been observed in one individual with malignant mesothelioma (De Rienzo 2015), and 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 Ala86Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Ala86Thr 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 evidence, it is unclear whether TP53 Ala86Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000633343 SCV000754565 uncertain significance Li-Fraumeni syndrome 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 86 of the TP53 protein (p.Ala86Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with malignant pleural mesothelioma (PMID: 26554828). ClinVar contains an entry for this variant (Variation ID: 141967). An experimental study in yeast has shown that this variant does not impair the transcriptional transactivation activity of the TP53 protein (PMID: 12826609, 10519380). 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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