ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.558T>A (p.Asp186Glu) (rs375275361)

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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 RCV000213742 SCV000273406 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000235477 SCV000293834 uncertain significance not provided 2017-01-11 criteria provided, single submitter clinical testing This variant is denoted TP53 c.558T>A at the cDNA level, p.Asp186Glu (D186E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAT>GAA). Although this variant has not, to our knowledge, been published in the literature as a germline variant, it has been reported as a somatic variant in oropharyngeal squamous cell carcinoma (Ibrahim 1999). This variant is reported as having functional transactivation in the International Agency for Research on Cancer TP53 databased based on functional assays by Kato et al. (2003). TP53 Asp186Glu was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Aspartic Acid and Glutamic Acid share similar properties, this is considered a conservative amino acid substitution. TP53 Asp186Glu occurs at a position that is not conserved and is located within 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 Asp186Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000470622 SCV000545295 uncertain significance Li-Fraumeni syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 186 of the TP53 protein (p.Asp186Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs375275361, ExAC 0.001%). This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 230006). An experimental study in yeast has shown that this missense change does not affect TP53 transcriptional 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.
Color RCV000213742 SCV000903937 likely benign Hereditary cancer-predisposing syndrome 2016-10-16 criteria provided, single submitter clinical testing

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