ClinVar Miner

Submissions for variant NM_001126112.2(TP53):c.946C>A (p.Pro316Thr) (rs772773208)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215470 SCV000273916 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-12 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient evidence
GeneDx RCV000235672 SCV000294080 uncertain significance not provided 2018-05-09 criteria provided, single submitter clinical testing This variant is denoted TP53 c.946C>A at the cDNA level, p.Pro316Thr (P316T) at the protein level, and results in the change of a Proline to a Threonine (CCC>ACC). This variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Pro316Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the nuclear localization signals (Shaulsky 1990, Pessoa 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether TP53 Pro316Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000467467 SCV000545286 uncertain significance Li-Fraumeni syndrome 2020-01-06 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 316 of the TP53 protein (p.Pro316Thr). The proline residue is moderately conserved and there is a small physicochemical difference between proline and threonine. This variant is present in population databases (rs772773208, ExAC 0.001%). This variant has not been reported in the literature in individuals with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 230382). An experimental study in yeast has shown that this variant impairs 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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