ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.877G>T (p.Gly293Trp) (rs587780076)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000213062 SCV000149650 uncertain significance not provided 2018-08-15 criteria provided, single submitter clinical testing This variant is denoted TP53 c.877G>T at the cDNA level, p.Gly293Trp (G293W) at the protein level, and results in the change of a Glycine to a Tryptophan (GGG>TGG). This variant was observed in an individual with adult onset sarcoma and in a 17 year-old with a glioblastoma who also had a diagnosis of neurofibromatosis type 1 (NF1), as well as in at least one breast cancer patient and in 1/3,610 individuals undergoing whole exome sequencing with a rare disease, severe obesity or neurodevelopmental disorder, with no specific information about cancer history provided (Chung 1991, Mitchell 2013, UK10K Consortium 2015, Tung 2016). 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) and was associated with transactivation activity similar to wildtype, without a dominant negative activity, in a yeast-based luciferase reporter assay (Monti 2011). TP53 Gly293Trp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether TP53 Gly293Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115741 SCV000187101 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000410614 SCV000488448 uncertain significance Li-Fraumeni syndrome 1 2016-04-07 criteria provided, single submitter clinical testing
Invitae RCV000462367 SCV000545297 uncertain significance Li-Fraumeni syndrome 2018-12-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with tryptophan at codon 293 of the TP53 protein (p.Gly293Trp). The glycine residue is moderately conserved and there is a large physicochemical difference between glycine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with glioblastoma and neurofibromatosis, sarcoma, and breast cancer (PMID: 1686725, 23894400, 26976419). ClinVar contains an entry for this variant (Variation ID: 127826). Experimental studies using a standardized yeast based transactivation assay show that this variant results in a small decrease in TP53 transcriptional transactivation activity (PMID: 17606709, 21343334). However, an additional study reports that this variant retains the functional activity of the p53 protein (PMID: 12826609). 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.
Color RCV000115741 SCV000691660 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-20 criteria provided, single submitter clinical testing

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