ClinVar Miner

Submissions for variant NM_001126112.2(TP53):c.665C>T (p.Pro222Leu) (rs146340390)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Ambry Genetics RCV000161032 SCV000215615 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-13 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000148907 SCV000254634 uncertain significance Li-Fraumeni syndrome 2019-12-13 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.
Counsyl RCV000411498 SCV000487965 uncertain significance Li-Fraumeni syndrome 1 2015-12-18 criteria provided, single submitter clinical testing
GeneKor MSA RCV000161032 SCV000822208 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color RCV000161032 SCV000903062 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-15 criteria provided, single submitter clinical testing
Mendelics RCV000989715 SCV001140257 benign Squamous cell carcinoma of the head and neck 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002287 SCV001160171 uncertain significance not specified 2018-12-12 criteria provided, single submitter clinical testing The TP53 c.665C>T; p.Pro222Leu variant (rs146340390) is reported in the literature in several individuals suspected of having Li-Fraumeni syndrome (Ruijs 2010) or Lynch syndrome (Yurgelun 2015), though it was also found in an individual not selected for a history of cancer (de Andrade 2017). This variant is reported in ClinVar (Variation ID: 161397) and is found on six chromosomes in the Genome Aggregation Database. The proline at codon 222 is moderately conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. In functional assays, the p.Pro222Leu variant exhibits comparable transcriptional activation activity to wildtype protein (Grochova 2008, Slovackova 2010). However, due to limited information, the clinical significance of this variant is uncertain at this time. References: de Andrade KC et al. Higher-than-expected population prevalence of potentially pathogenic germline TP53 variants in individuals unselected for cancer history. Hum Mutat. 2017 Dec;38(12):1723-1730. Grochova D et al. Analysis of transactivation capability and conformation of p53 temperature-dependent mutants and their reactivation by amifostine in yeast. Oncogene. 2008 Feb 21;27(9):1243-52. Ruijs MW et al. TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. J Med Genet. 2010 Jun;47(6):421-8. Slovackova J et al. Transactivation by temperature-dependent p53 mutants in yeast and human cells. Cell Cycle. 2010 Jun 1;9(11):2141-8. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20.
CSER _CC_NCGL, University of Washington RCV000148907 SCV000190653 likely benign Li-Fraumeni syndrome 2014-06-01 no assertion criteria provided research

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