ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.886C>T (p.His296Tyr) (rs672601296)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000774785 SCV000908783 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000486480 SCV000571798 uncertain significance not provided 2016-09-23 criteria provided, single submitter clinical testing This variant is denoted TP53 c.886C>T at the cDNA level, p.His296Tyr (H296Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAC>TAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant is reported as having super-functional transactivation in the International Agency for Research on Cancer TP53 database, based on functional assays by Kato et al. (2003), defined as tranactivation activity greater than wild type. TP53 His296Tyr 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 Histidine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 His296Tyr occurs at a position that is not conserved and is located in the DNA binding domain (Bode 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether TP53 His296Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000633378 SCV000754600 uncertain significance Li-Fraumeni syndrome 2017-10-24 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 296 of the TP53 protein (p.His296Tyr). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine. 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: 132973). Experimental studies in yeast have shown that this missense change disrupts 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.
Laboratory of Translational Genomics, National Cancer Institute RCV000119375 SCV000154282 not provided Sarcoma no assertion provided not provided

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