ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.100C>G (p.Pro34Ala) (rs786201968)

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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 RCV000165887 SCV000216640 uncertain significance Hereditary cancer-predisposing syndrome 2014-09-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Color RCV000165887 SCV000691570 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-08 criteria provided, single submitter clinical testing
GeneDx RCV000483753 SCV000573111 uncertain significance not provided 2017-02-08 criteria provided, single submitter clinical testing This variant is denoted TP53 c.100C>G at the cDNA level, p.Pro34Ala (P34A) at the protein level, and results in the change of a Proline to an Alanine (CCC>GCC). This variant is reported as having functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Pro34Ala 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 Proline and Alanine differ in some properties, this is considered a semi-conservative amino acid substitution. TP53 Pro34Ala occurs at a position that is not conserved and is located in the transactivation domain and the nuclear export signal region (Zhang 2001, Bode 2004, Pessoa 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether TP53 Pro34Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000205889 SCV000261187 uncertain significance Li-Fraumeni syndrome 2015-10-13 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 34 of the TP53 protein (p.Pro34Ala). The proline residue is weakly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature. ClinVar contains an entry for this variant (Variation ID: 186313). 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 tolerated, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change that is not predicted to affect protein function or cause disease. However, the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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