ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.314G>A (p.Gly105Asp) (rs587781504)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129479 SCV000184249 likely pathogenic Hereditary cancer-predisposing syndrome 2015-06-24 criteria provided, single submitter clinical testing Deficient protein function in appropriate functional assay(s);Other strong data supporting pathogenic classification;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Co-occurence with a mutation in another gene that clearly explains a proband's phenotype
GeneDx RCV000201000 SCV000211738 likely pathogenic not provided 2015-08-24 criteria provided, single submitter clinical testing This variant is denoted TP53 c.314G>A at the cDNA level, p.Gly105Asp (G105D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGC>GAC). While TP53 Gly105Asp has not been reported in the literature as a germline variation to our knowledge, it has been observed as a somatic variant. Another missense variant at the same residue, Gly105Cys, has been observed in an individual with breast cancer who met Chompret criteria for Li-Fraumeni syndrome (Bendig 2004). Functional assays show that TP53 Gly105Asp is nonfunctional based on the loss of transcriptional activity of p53 in a yeast-based functional assay (Dekairelle 2005). However, this variant is reported as having partial functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Gly105Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glycine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Gly105Asp occurs at a position that is conserved across species and is located in the DNA-binding domain and region of interaction with WWOX, HIPK1 and ZNF385A (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the current evidence, we consider TP53 Gly105Asp to be a likely pathogenic variant.
Invitae RCV000228756 SCV000285185 uncertain significance Li-Fraumeni syndrome 2015-12-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 105 of the TP53 protein (p.Gly105Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TP53-related disease as a germline variant. ClinVar contains an entry for this variant (Variation ID: 141114). An experimental study has shown that this variant partially affects transactivation activity of TP53 protein in yeast-based assays (PMID: 12826609). In addition, 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. In summary, this is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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