ClinVar Miner

Submissions for variant NM_001126112.2(TP53):c.480G>A (p.Met160Ile) (rs772354334)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000218200 SCV000274415 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-05 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000485502 SCV000569877 uncertain significance not provided 2017-09-29 criteria provided, single submitter clinical testing This variant is denoted TP53 c.480G>A at the cDNA level, p.Met160Ile (M160I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATA). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or benign polymorphism; however, it has been reported as a somatic variant in multiple different tumor types (Waridel 1997, Lukas 2001, Janku 2014, Umemura 2014, Forbes 2015). This variant is reported as having partially functional transactivation capacity in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Met160Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Methionine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. TP53 Met160Ile occurs at a position that is not conserved and is located in the DNA binding domain (Bode 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether TP53 Met160Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000542402 SCV000629827 uncertain significance Li-Fraumeni syndrome 2018-11-19 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 160 of the TP53 protein (p.Met160Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs772354334, ExAC 0.001%). This variant has been observed in an individual affected with breast cancer (PMID: 29785153). ClinVar contains an entry for this variant (Variation ID: 230758). Transactivation studies performed in yeast cell lines have shown that this variant retains partial TP53 transcrtiptional transactivation function (PMID: 12826609, 9627118). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, 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.
Color RCV000218200 SCV000686742 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-07 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000485502 SCV000806240 uncertain significance not provided 2017-01-10 criteria provided, single submitter clinical testing
GeneKor MSA RCV000218200 SCV000822207 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.