ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.572C>G (p.Pro191Arg) (rs587778718)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219468 SCV000276419 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000219468 SCV000686752 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing
Counsyl RCV000662561 SCV000785162 uncertain significance Li-Fraumeni syndrome 1 2017-05-10 criteria provided, single submitter clinical testing
GeneDx RCV000766937 SCV000149636 uncertain significance not provided 2016-04-11 criteria provided, single submitter clinical testing This variant is denoted TP53 c.572C>G at the cDNA level, p.Pro191Arg (P191R) at the protein level, and results in the change of a Proline to an Arginine (CCT>CGT). This variant has not been reported, to our knowledge, as a germline pathogenic variant or polymorphism; however, the International Agency for Research on Cancer (IARC) TP53 database lists this variant as a somatic change with functional transactivation activity in yeast (Petitjean 2007). While TP53 Pro191Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, it was identified in 1/681 healthy individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. Since Proline and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Pro191Arg occurs at a position that is conserved in mammals and is located within the DNA-binding domain and within a region required for interaction with multiple proteins (Bode 2004, UniProt). In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether TP53 Pro191Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
ITMI RCV000122174 SCV000086389 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000205751 SCV000261596 uncertain significance Li-Fraumeni syndrome 2018-07-31 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 191 of the TP53 protein (p.Pro191Arg). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and arginine. This variant is present in population databases (rs587778718, ExAC 0.009%). This variant has been reported in 3 members of a family affected with Li-Fraumeni syndrome. However, the variant did not segregate with disease in one of these individuals (PMID: 27297285). ClinVar contains an entry for this variant (Variation ID: 127816). Experimental studies performed in yeast showed that this missense variant does not affect TP53 transactivation activity (PMID: 12826609). However, another study performed in human cell lines showed that this variant results in a significant decrease of TP53 transactivation activity (PMID: 27297285). The clinical significance of these results are unknown. 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.

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