ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.214C>G (p.Pro72Ala) (rs587782769)

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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 RCV000132297 SCV000187382 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-24 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification;Insufficient or conflicting evidence
Counsyl RCV000409340 SCV000487877 uncertain significance Li-Fraumeni syndrome 1 2015-11-24 criteria provided, single submitter clinical testing
Invitae RCV000473980 SCV000545301 uncertain significance Li-Fraumeni syndrome 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 72 of the TP53 protein (p.Pro72Ala). The proline residue is weakly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs587782769, ExAC 0.01%). This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 142854). Experimental studies have shown that this missense change does not impact TP53 transcriptional activity (PMID: 23713777, 12826609). 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.
GeneDx RCV000478624 SCV000566998 uncertain significance not provided 2016-05-02 criteria provided, single submitter clinical testing This variant is denoted TP53 c.214C>G at the cDNA level, p.Pro72Ala (P72A) at the protein level, and results in the change of a Proline to an Alanine (CCC>GCC). This variant was observed in the tissue of a hepatocellular carcinoma and a high-grade glioblastoma as a somatic variant (Derakhshandeh-Peykar 2011, Ji 2014). TP53 Pro72Ala 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 Pro72Ala occurs at a position that is not conserved, with Alanine being the naturally occurring amino acid at this position in a few mammals, and is located in the SH3 domain (Bode 2004). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether TP53 Pro72Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000132297 SCV000903896 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing

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