ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.851C>T (p.Thr284Ile) (rs863224685)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197045 SCV000254641 uncertain significance Li-Fraumeni syndrome 2017-09-25 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 284 of the TP53 protein (p.Thr284Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. 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: 216471). An experimental study in yeast has shown that this missense change does not affect TP53 transactivation activity (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.
GeneDx RCV000483278 SCV000567137 uncertain significance not provided 2015-07-10 criteria provided, single submitter clinical testing This variant is denoted TP53 c.851C>T at the cDNA level, p.Thr284Ile (T284I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant was observed in a patient with a personal history of a Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015). TP53 Thr284Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Thr284Ile occurs at a position that is conserved in mammals and is located within the CCAR2 interaction domain (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 Thr284Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000569733 SCV000664389 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence,Other data supporting benign classification

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