ClinVar Miner

Submissions for variant NM_001126112.2(TP53):c.482C>A (p.Ala161Asp) (rs1064795691)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481512 SCV000571725 likely pathogenic not provided 2018-10-19 criteria provided, single submitter clinical testing This variant is denoted TP53 c.482C>A at the cDNA level, p.Ala161Asp (A161D) at the protein level, and results in the change of an Alanine to an Aspartic Acid (GCC>GAC). This variant has not, to our knowledge, been published in the literature as a germline variant, but has been reported as a somatic variant in breast, hematologic, and other tumors and cell lines (Kang 2001, Bally 2014, Sallman 2016, COSMIC database). This variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003) and has also been found to lead to loss of growth suppression activity, but no dominant-negative effect (Marutani 1999, Kotler 2018). TP53 Ala161Asp was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available evidence, we consider TP53 Ala161Asp to be a likely pathogenic variant.
Invitae RCV000552464 SCV000629828 uncertain significance Li-Fraumeni syndrome 2017-04-06 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 161 of the TP53 protein (p.Ala161Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature as a germline variant in individuals with a TP53-related disease. An experimental study has shown that this missense change disrupts TP53 transactivational activity in yeast (PMID: 12826609). In summary, this variant is a rare missense change with that disrupts protein function in yeast and is absent from the population, but has also not been reported in the germline of any affected individual. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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