ClinVar Miner

Submissions for variant NM_001126112.2(TP53):c.473G>C (p.Arg158Pro) (rs587782144)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236862 SCV000293524 likely pathogenic not provided 2018-11-13 criteria provided, single submitter clinical testing This variant is denoted TP53 c.473G>C at the cDNA level, p.Arg158Pro (R158P) at the protein level, and results in the change of an Arginine to a Proline (CGC>CCC). This variant has been observed in at least one individual reported to have Li-Fraumeni syndrome (Morgan 2010). On functional interrogation, TP53 Arg158Pro has been shown to impact transactivation, growth suppression, and cause a dominant-negative effect (Brachmann 1996, Dearth 2007, Kotler 2018). Consistent with these results, 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 Arg158Pro 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 Arg158Pro to be a likely pathogenic variant.
Invitae RCV000548853 SCV000629825 uncertain significance Li-Fraumeni syndrome 2017-07-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 158 of the TP53 protein (p.Arg158Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Li-fraumeni syndrome (PMID: 20127978).  ClinVar contains an entry for this variant (Variation ID: 246118). 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 and their clinical significance is uncertain. A different missense substitution at this codon (pArg158His) has been determined to be pathogenic (PMID: 20522432, 17606709, 21601526, 18685109, 25584008, 21343334,). This suggests that the arginine residue is critical for TP53 protein function and that other missense substitutions at this position may also be pathogenic. 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.
Mendelics RCV000989719 SCV001140261 likely pathogenic Squamous cell carcinoma of the head and neck 2019-05-28 criteria provided, single submitter clinical testing

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