ClinVar Miner

Submissions for variant NM_001126112.2(TP53):c.760A>G (p.Ile254Val) (rs746601313)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000477424 SCV000545356 uncertain significance Li-Fraumeni syndrome 2019-12-03 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 254 of the TP53 protein (p.Ile254Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs746601313, ExAC 0.001%). This variant has been reported in three individuals affected with lung cancer (PMID: 27242894), in a family with suspected Li-Fraumeni syndrome (PMID: 21348412), in individuals affected with uveal melanoma (PMID: 29769598), and in two individuals undergoing genetic testing unselected for cancer history (PMID: 28861920). ClinVar contains an entry for this variant (Variation ID: 406605). An experimental study in yeast has shown that this variant does not impair the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). This variant disrupts the p.Ile254 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29070607). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. 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 RCV000485986 SCV000566316 uncertain significance not provided 2018-02-15 criteria provided, single submitter clinical testing This variant is denoted TP53 c.760A>G at the cDNA level, p.Ile254Val (I254V) at the protein level, and results in the change of an Isoleucine to a Valine (ATC>GTC). This variant has been observed in at least one family suggestive of Li-Fraumeni syndrome (Foretova 2010). TP53 Ile254Val 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 Ile254Valwas 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether TP53 Ile254Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000573924 SCV000664384 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-19 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000573924 SCV000686769 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-19 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765398 SCV000896673 uncertain significance Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Carcinoma of colon; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma 2018-10-31 criteria provided, single submitter clinical testing

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