ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.1150A>G (p.Met384Val) (rs730882009)

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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 RCV000161040 SCV000216174 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000213071 SCV000211770 uncertain significance not specified 2017-04-03 criteria provided, single submitter clinical testing This variant is denoted TP53 c.1150A>G at the cDNA level, p.Met384Val (M384V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. TP53 Met384Val 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 Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. TP53 Met384Val occurs at a position that is moderately conserved across species and is located in the basic (repression of DNA-binding) region, which is also a region responsible for interaction with Coactivator-Associated Arginine Methyltransferase 1 (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether TP53 Met384Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587685 SCV000697427 uncertain significance not provided 2016-10-28 criteria provided, single submitter clinical testing Variant summary: The TP53 c.1150A>G (p.Met384Val) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. This variant is absent in 121408 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000195684 SCV000254626 uncertain significance Li-Fraumeni syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 384 of the TP53 protein (p.Met384Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with suspected Lynch syndrome  (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 182939). 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.

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