ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.794T>C (p.Leu265Pro) (rs879253942)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000564617 SCV000672371 pathogenic Hereditary cancer-predisposing syndrome 2018-03-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Other strong data supporting pathogenic classification,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Counsyl RCV000662855 SCV000785730 likely pathogenic Li-Fraumeni syndrome 1 2017-11-10 criteria provided, single submitter clinical testing
GeneDx RCV000235981 SCV000292887 pathogenic not provided 2015-05-12 criteria provided, single submitter clinical testing This pathogenic variant is denoted TP53 c.794T>C at the cDNA level, p.Leu265Pro (L265P) at the protein level, and results in the change of a Leucine to a Proline (CTG>CCG). This variant was observed in at least two families with classic Li-Fraumeni syndrome (Cornelis 1997, Ruijs 2010). Several yeast based functional assays have demonstrated that this mutation severely impacts p53 function and stability (Brachmann 1996, Dearth 2007, Monti 2007, Monti 2011). In addition, this mutation conferred reduced DNA binding activity and expression of downstream target genes in an in vitro functional assay (Malcikova 2010). 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 Leu265Pro 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 Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. TP53 Leu265Pro occurs at a position that is conserved across species and is located in the DNA binding domain and region of interaction with HIPK1, ZNF385A, AXIN1 and E4F1 (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the current evidence, we consider this variant to be pathogenic.
Invitae RCV000554509 SCV000629871 pathogenic Li-Fraumeni syndrome 2018-02-23 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 265 of the TP53 protein (p.Leu265Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two families affected with Li-Fraumeni syndrome (PMID: 9067756, 20522432). In one of the families, this variant segregated with disease (PMID: 9067756). ClinVar contains an entry for this variant (Variation ID: 245777). Experimental in vitro studies have shown that this missense change results in almost null TP53 DNA-binding and transactivation activity, and that it may act in a dominant-negative manner in decreasing TP53 wild-type activity (PMID: 12826609, 16861262, 17606709, 20128691, 21343334). For these reasons, this variant has been classified as Pathogenic.

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