ClinVar Miner

Submissions for variant NM_001126112.2(TP53):c.509C>T (p.Thr170Met) (rs779000871)

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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 RCV000163119 SCV000213630 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-27 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000206777 SCV000260532 uncertain significance Li-Fraumeni syndrome 2019-09-21 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 170 of the TP53 protein (p.Thr170Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs779000871, ExAC 0.01%). This variant has been reported in an individual with rhabodomyosarcoma, with no family history of Li-Fraumeni or Li-Fraumeni-like syndrome (PMID: 22653678). ClinVar contains an entry for this variant (Variation ID: 184014). An experimental study in yeast has shown that this variant partially impairs the transcriptional transactivation activity of the TP53 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.
GeneDx RCV000478196 SCV000567645 uncertain significance not provided 2018-03-13 criteria provided, single submitter clinical testing This variant is denoted TP53 c.509C>T at the cDNA level, p.Thr170Met (T170M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant was reported in a child with an embryonal rhabdomyosarcoma whose family history was not consistent with Li-Fraumeni or Li-Fraumeni-like syndrome (Magnusson 2012). TP53 Thr170Met is reported as having partially functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). TP53 Thr170Met 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 information, it is unclear whether TP53 Thr170Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000163119 SCV000686747 uncertain significance Hereditary cancer-predisposing syndrome 2015-07-15 criteria provided, single submitter clinical testing
Counsyl RCV000662787 SCV000785596 uncertain significance Li-Fraumeni syndrome 1 2017-10-02 criteria provided, single submitter clinical testing

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