ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.749C>T (p.Pro250Leu) (rs1064794311)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479937 SCV000568759 likely pathogenic not provided 2018-05-09 criteria provided, single submitter clinical testing This variant is denoted TP53 c.749C>T at the cDNA level, p.Pro250Leu (P250L) at the protein level, and results in the change of a Proline to a Leucine (CCC>CTC). This variant has been reported as a somatic variant in osteosarcoma, rhabdomyosarcoma, chronic lymphocytic leukemia, and other tumors and cell lines, but has not been reported as a germline variant to our knowledge (Toguchida 1992, Gokgoz 2001, Pekova 2011, COSMIC). TP53 Pro250Leu 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) and has also been described as demonstrating reduced or absent transactivation capabilities in other studies (Campomenosi 2001, Maurici 2001, Monti 2002). In addition, this variant was shown to cause cytoplasmic protein aggregation, resulting in impaired nuclear import and destabilization in HT-1376 bladder cells (Xu 2011). TP53 Pro250Leu was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available evidence, we consider TP53 Pro250Leu to be a likely pathogenic variant.
Invitae RCV000547538 SCV000629865 uncertain significance Li-Fraumeni syndrome 2017-07-07 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 250 of the TP53 protein (p.Pro250Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). Although this variant has been reported as a somatic variant in the tumors of several individuals affected with various cancers (PMID: 20634494, 15523690, 21232794, 24009708, 22040862, 21901162, 27150160, 26475379), it has not been reported in the germline of any individual with a TP53 related disease. Experimental studies of transcriptional activity in yeast using multiple promoters have shown that this missense change is non-functional and may act in a dominant negative manner (PMID: 12826609, 11896595, 11429705, 11429700, 14559903). An additional study also shows that this missense change mislocalizes when transfected into cells, forming aggregates that sequester wild-type TP53 away from its normal nuclear location, which is predicted to disrupt TP53 protein function (PMID: 21445056). In summary, this variant is a rare missense change that has been shown to disrupt protein function in vitro. While it is absent from the population and has been reported as a somatic variant in affected individuals, it has not been reported in the germline of an affected individual. Therefore, without additional genetic data, this variant has been classified as a Variant of Uncertain Significance.

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