ClinVar Miner

Submissions for variant NM_001126112.2(TP53):c.464C>G (p.Thr155Ser) (rs786202752)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165724 SCV000216465 likely benign Hereditary cancer-predisposing syndrome 2019-03-22 criteria provided, single submitter clinical testing Other strong data supporting benign classification;Other data supporting benign classification;In silico models in agreement (benign)
Invitae RCV000804037 SCV000943929 uncertain significance Li-Fraumeni syndrome 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 155 of the TP53 protein (p.Thr155Ser). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 186179). An experimental study in yeast has shown that this variant does not impair the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000986051 SCV001134870 likely benign not provided 2019-04-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001192618 SCV001360867 uncertain significance not specified 2019-05-02 criteria provided, single submitter clinical testing Variant summary: TP53 c.464C>G (p.Thr155Ser) results in a conservative amino acid change located in the p53 DNA-binding domain (IPR011615) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251290 control chromosomes (gnomAD exomes). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.464C>G has been reported in the literature in Malignant Peripheral Nerve Sheath tumors (MPNSTs) (Verdijk_2010 citing Mawrin_2002) and as a germline likely benign variant among individuals in gnomAD (Andrade_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Carlsson_2009). The IARC database reports this as a functional variant based on overall transcriptional activity (TA) on 8 different promoters as measured in yeast assays by Kato et al. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

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