ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.884C>T (p.Pro295Leu) (rs751713111)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000774786 SCV000908784 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-01 criteria provided, single submitter clinical testing
GeneDx RCV000486525 SCV000570029 uncertain significance not provided 2018-09-06 criteria provided, single submitter clinical testing This variant is denoted TP53 c.884C>T at the cDNA level, p.Pro295Leu (P295L) at the protein level, and results in the change of a Proline to a Leucine (CCT>CTT). While this variant has been reported in breast tissue, it has not, to our knowledge, been reported in the literature as a pathogenic or benign germline variant (Al-Qasem 2011). TP53 Pro295Leu is reported as having ?super? transactivation function (transactivation capacities >100% for multiple reporters) in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Pro295Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 Pro295Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000633374 SCV000754596 uncertain significance Li-Fraumeni syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 295 of the TP53 protein (p.Pro295Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs751713111, 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: 420974). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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