ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.332T>C (p.Leu111Pro) (rs1057519997)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000459042 SCV000545305 uncertain significance Li-Fraumeni syndrome 2016-06-11 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 111 of the TP53 protein (p.Leu111Pro). 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) and has not been reported in the literature in individuals with a TP53-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
GeneDx RCV000480700 SCV000565622 likely pathogenic not provided 2018-11-13 criteria provided, single submitter clinical testing This variant is denoted TP53 c.332T>C at the cDNA level, p.Leu111Pro (L111P) at the protein level, and results in the change of a Leucine to a Proline (CTG>CCG). While this variant has not, to our knowledge, been reported in the literature as a germline variant, it has been observed as a somatic variant in multiple tumor types (Goh 1995, Kurniawan 2006, COSMIC). On functional interrogation, TP53 Leu111Pro has demonstrated loss of transcriptional activation and growth suppression activities (Dekairelle 2005, Kotler 2018), and 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 Leu111Pro 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 currently available evidence, we consider TP53 Leu111Pro to be a likely pathogenic variant.
Database of Curated Mutations (DoCM) RCV000441916 SCV000508812 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425579 SCV000508813 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435918 SCV000508814 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442239 SCV000508815 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425862 SCV000508816 likely pathogenic Chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435274 SCV000508817 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417617 SCV000508818 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428739 SCV000508819 likely pathogenic Neoplasm of the breast 2016-05-31 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785496 SCV000924068 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

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