ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.845G>T (p.Arg282Leu) (rs730882008)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000161038 SCV000214901 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
GeneDx RCV000213059 SCV000211761 uncertain significance not provided 2014-07-11 criteria provided, single submitter clinical testing This variant is denoted TP53 c.845G>T at the cDNA level, p.Arg282Leu (R282L) at the protein level, and results in the change of an Arginine to a Leucine (CGG>CTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant has been observed as a somatic variation in a number of different cancer types (COSMIC). TP53 Arg282Leu 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 Arginine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Arg282Leu occurs at a position that is well conserved across species and is located in the DNA binding domain and the region of interaction with HIPK1, ZNF385A, FBXO42, AXIN1, and E4F1 (UniProt). 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 Arg282Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000633381 SCV000754603 uncertain significance Li-Fraumeni syndrome 2017-09-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 282 of the TP53 protein (p.Arg282Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 182938). An experimental study using a yeast-based functional assay has shown that this missense change does not affect the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). A different missense substitution at this codon (p.Arg282Trp) has been determined to be pathogenic (PMID: 25584008, 21305319, 22672556, 19468865, 17606709). 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.

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