ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.655C>T (p.Pro219Ser) (rs879253894)

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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 RCV000492115 SCV000581085 likely pathogenic Hereditary cancer-predisposing syndrome 2017-08-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Counsyl RCV000576805 SCV000677775 likely pathogenic Li-Fraumeni syndrome 1 2016-12-28 criteria provided, single submitter clinical testing
GeneDx RCV000236313 SCV000292697 uncertain significance not specified 2017-06-19 criteria provided, single submitter clinical testing This variant is denoted TP53 c.655C>T at the cDNA level, p.Pro219Ser (P219S) at the protein level, and results in the change of a Proline to a Serine (CCC>TCC). Although this variant seems to have been reported several times in the literature, many reports describe the same French-Canadian family with two cases of pediatric-onset adrenocortical carcinoma (Wagner 1994, Wilkin 2000, Arcand 2015, Wasserman 2015). To date no other family members have been reported with early-onset breast or other cancers within the Li-Fraumeni spectrum, including a 30-year-old obligate carrier female. TP53 Pro219Ser has also been reported in an individual with a neuroblastoma diagnosed after 18 months of age (Pugh 2013). This variant 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 Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Pro219Ser occurs at a position that is conserved across species and is located within the DNA binding domain and region of interaction with multiple proteins (UniProt). While in silico analyses predict that this variant is probably damaging to protein structure and function, functional analyses interrogating this variantÂ’s impact on transcriptional activity - a key activity of the p53 protein - have demonstrated conflicting results. Malcikova et al. (2010) found that TP53 Pro219Ser decreased DNA-binding ability, and this variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). However, Wasserman et al. (2015) found that this variant only caused a slight decrease in transcriptional activity compared to wild-type and retained partial ability to interfere with colony formation on a growth reduction assay. Monti et al. (2011) described TP53 Pro219Ser as a partial" rather than "severe" deficiency allele due to mean transcriptional activity of greater than 25% across several p53-responsive elements. Additionally, both Wasserman et al. (2015) and Monti et al. (2011) did not find this variant capable of causing a dominant-negative effect. Based on currently available information, it is unclear whether TP53 Pro219Ser is pathogenic or benign. We consider it to be a variant of uncertain significance."

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