ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.1040C>A (p.Ala347Asp) (rs397516434)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492626 SCV000581153 likely pathogenic Hereditary cancer-predisposing syndrome 2013-11-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification
GeneDx RCV000255021 SCV000321974 pathogenic not provided 2018-05-29 criteria provided, single submitter clinical testing This variant is denoted TP53 c.1040C>A at the cDNA level, p.Ala347Asp (A347D) at the protein level, and results in the change of an Alanine to an Aspartic Acid (GCC>GAC). This variant has been reported in at least two families with sarcoma and/or breast cancer (Villani 2016). Although in silico analysis supports that this variant does not alter protein structure/function, TP53 Ala347Asp has been demonstrated to decrease transactivation activity and prohibit tetramer formation in a yeast-based in vitro assay (Kawaguchi 2005). This variant is also 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). TP53 Ala347Asp was not observed in large population cohorts (Lek 2016). This variant is located within the tetramerization domain and the nuclear export signal region (Zhang 2001, Bode 2004, Pessoa 2014). Based on currently available evidence, we consider TP53 Ala347Asp to be pathogenic.
Invitae RCV000468537 SCV000545289 uncertain significance Li-Fraumeni syndrome 2016-09-20 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 347 of the TP53 protein (p.Ala347Asp). 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). This variant has been reported in the literature in two unrelated individuals being tested for suspected Li-Fraumeni syndrome. The first individual was affected with high-grade pleomorphic sarcoma at age 19 years, while the second individual was diagnosed with breast cancer at 49 years old. No additional family members were reported to have cancer (PMID: 27501770). This variant was also observed in the IARC TP53 database in a large family affected with cancer, although the specifics of the related cancers were unspecified for many of the family members (PMID: 17311302). ClinVar contains an entry for this variant (Variation ID: 43587). Experimental studies have shown that this missense change affects the ability of TP53 to form a tetramer and transcriptionally transactivate its targets in a yeast-based functional assay (PMID: 16007150, 12826609). In summary, this variant is a rare missense change that has been shown to disrupt TP53 protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Without further genetic data, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036529 SCV000060184 uncertain significance not specified 2008-07-21 no assertion criteria provided clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000255021 SCV000602259 likely pathogenic not provided 2017-03-29 criteria provided, single submitter clinical testing

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