ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.728T>C (p.Met243Thr) (rs730882006)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000161035 SCV000211757 uncertain significance not provided 2014-07-29 criteria provided, single submitter clinical testing This variant is denoted TP53 c.728T>C at the cDNA level, p.Met243Thr (M243T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has not been published as a germline pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. However, it has been reported as a somatic change in various tumor types including breast and soft tissue sarcoma according to the Catalogue of Somatic Mutations in Cancer. A prediction model based on sequence conservation and structural calculations predicted TP53 Met243Thr may impact binding with certain promoters (Carlsson 2009). TP53 Met243Thr 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 Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Met243Thr occurs at a position that is moderately conserved in mammals and is located in the DNA binding domain and interacts with HIPK1, ZNF385A, AXIN1, and 53BP2 SH3 (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 Met243Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000222280 SCV000273434 likely pathogenic Hereditary cancer-predisposing syndrome 2015-01-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes),Other data supporting pathogenic classification
Invitae RCV000686581 SCV000814104 uncertain significance Li-Fraumeni syndrome 2018-03-16 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 243 of the TP53 protein (p.Met243Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. 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: 182936). 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. An experimental study in yeast has shown that this variant 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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