ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.569C>T (p.Pro190Leu) (rs876660825)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484792 SCV000565623 uncertain significance not provided 2014-10-21 criteria provided, single submitter clinical testing This variant is denoted TP53 c.569C>T at the cDNA level, p.Pro190Leu (P190L) at the protein level, and results in the change of a Proline to a Leucine (CCT>CTT). Although this variant has been reported as a somatic variant in several cancer types, it has not been reported as a germline pathogenic variant to our knowledge (COSMIC). Functional studies revealed subtle transactivation defects under some but not all experimental conditions (Jordan 2010). TP53 Pro190Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. TP53 Pro190Leu occurs at a position that is well conserved across species and is located in DNA-binding domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether TP53 Pro190Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000551566 SCV000629842 uncertain significance Li-Fraumeni syndrome 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 190 of the TP53 protein (p.Pro190Leu). 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). This variant has been reported in a family with Li-Fraumeni syndrome (LFS), but currently there is insufficient evidence whether it segregates with disease or not (PMID: 17311302). ClinVar contains an entry for this variant (Variation ID: 418517). Experimental studies using yeast and cell line models have shown that this change partially alters the transcriptional activity of the TP53 protein (PMID: 20407015, 12826609, 23713777). In summary, this variant has uncertain impact on TP53 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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