ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.970G>C (p.Asp324His) (rs1064794810)

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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 RCV000573045 SCV000664401 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000573045 SCV000910430 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-01 criteria provided, single submitter clinical testing
GeneDx RCV000478385 SCV000569995 uncertain significance not provided 2016-08-09 criteria provided, single submitter clinical testing This variant is denoted TP53 c.970G>C at the cDNA level, p.Asp324His (D324H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAT>CAT). This variant has been identified in an individual with mesothelioma (Meric-Bernstam 2016). TP53 Asp324His 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 Aspartic Acid and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Asp324His occurs at a position where amino acids with properties similar to Aspartic Acid are tolerated across species and is located in the nuclear localization signals and the tetramerization domain (Shaulsky 1990, Bode 2004, Pessoa 2014). 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 Asp324His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000555965 SCV000629891 uncertain significance Li-Fraumeni syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 324 of the TP53 protein (p.Asp324His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual affected with mesothelioma (PMID: 26787237). ClinVar contains an entry for this variant (Variation ID: 420950). 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. 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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