ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.607G>A (p.Val203Met) (rs730882003)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000161031 SCV000211752 uncertain significance not provided 2014-04-08 criteria provided, single submitter clinical testing This variant is denoted TP53 c.607G>A at the cDNA level, p.Val203Met (V203M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has been identified in the tumors of multiple individuals (Bromidge 2008, Carr-Wilkinson 2010, Van Maerken 2011); however, this TP53 Val203Met has not been reported as a germline pathogenic variant. TP53 Val203Met 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 Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. TP53 Val203Met occurs at a position that is highly variable across species and is located in the DNA binding domain and the region required for interaction with ZNF385A, FBXO42, and AXIN1 (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether TP53 Val203Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000460914 SCV000545268 uncertain significance Li-Fraumeni syndrome 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 203 of the TP53 protein (p.Val203Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. 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: 182933). An experimental study in yeast has shown that this variant partially impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). 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.
Ambry Genetics RCV000492177 SCV000581111 uncertain significance Hereditary cancer-predisposing syndrome 2015-10-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence

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