ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.665C>T (p.Pro222Leu) (rs146340390)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000161032 SCV000215615 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000148907 SCV000190653 likely benign Li-Fraumeni syndrome 2014-06-01 no assertion criteria provided research
Color RCV000161032 SCV000903062 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-31 criteria provided, single submitter clinical testing
Counsyl RCV000411498 SCV000487965 uncertain significance Li-Fraumeni syndrome 1 2015-12-18 criteria provided, single submitter clinical testing
GeneDx RCV000213056 SCV000211754 uncertain significance not provided 2018-11-02 criteria provided, single submitter clinical testing This variant is denoted TP53 c.665C>T at the cDNA level, p.Pro222Leu (P222L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). This variant was observed in an individual diagnosed with a childhood rhabdomyosarcoma and in at least one individual undergoing genetic panel testing for suspicion of Lynch syndrome (Ruijs 2010, Yurgelun 2015). Functional studies have revealed transcriptional activation and growth suppression activities comparable to wild-type (Grochova 2008, Slovackova 2010, Iggo 2013, Kotler 2018). In addition, 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 Pro222Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether TP53 Pro222Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000161032 SCV000822208 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000148907 SCV000254634 uncertain significance Li-Fraumeni syndrome 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 222 of the TP53 protein (p.Pro222Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs146340390, ExAC 0.002%). This variant has been reported in an individual suspected of having Li-Fraumeni syndrome (PMID: 20522432). It has also been reported in the germline of one individual affected with chronic lymphocytic leukemia (PMID: 28230820), and an individual suspected of having Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 161397). Experimental studies have shown that this missense change does not substantially alter the transcriptional transactivation activity of the TP53 protein (PMID: 12826609, 17311302, 17724467, 23897043). 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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