ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.107C>A (p.Pro36Gln) (rs587781866)

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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 RCV000130183 SCV000185020 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000130183 SCV000908804 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-17 criteria provided, single submitter clinical testing
Counsyl RCV000662689 SCV000785414 uncertain significance Li-Fraumeni syndrome 1 2017-07-25 criteria provided, single submitter clinical testing
GeneDx RCV000213046 SCV000211734 uncertain significance not provided 2014-06-27 criteria provided, single submitter clinical testing This variant is denoted TP53 c.107C>A at the cDNA level, p.Pro36Gln (P36Q) at the protein level, and results in the change of a Proline to a Glutamine (CCG>CAG). TP53 Pro36Gln has been observed as a somatic mutation in hematopoietic malignancy and reported to demonstrate functional transactivation activity similar to wild type in a yeast assay (IARC TP53 Database, Shiraishi 2004). TP53 Pro36Gln 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 Proline and Glutamine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Pro36Gln occurs at a position that is variable across species and is located in the transcription activation domain and region of interaction with HRMT1L2 (UniProt). Multiple in silico models predict formation of a new, cryptic splice acceptor site of equivalent strength as the natural splice acceptor site. In addition, 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 Pro36Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000469733 SCV000545275 uncertain significance Li-Fraumeni syndrome 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces proline with glutamine at codon 36 of the TP53 protein (p.Pro36Gln). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 141597). An experimental study in yeast has shown that this variant does not impair the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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