ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.946C>A (p.Pro316Thr) (rs772773208)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215470 SCV000273916 uncertain significance Hereditary cancer-predisposing syndrome 2015-02-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 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 2018-10-31 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%) but has not been reported in the literature in individuals with a TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 230382). An experimental study testing TP53 transactivation activity on 8 different promoters in yeast has shown that this missense change is non-functional (PMID: 12826609). In summary, this variant is a rare missense change that has been shown to affect protein function. However, this variant is also present in the general population and affected individuals have not been reported. For these reasons, this change has been classified as a Variant of Uncertain Significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.