ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.634T>A (p.Phe212Ile) (rs1064795766)

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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 RCV000492242 SCV000581091 uncertain significance Hereditary cancer-predisposing syndrome 2012-12-04 criteria provided, single submitter clinical testing
Color RCV000492242 SCV000910458 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing
GeneDx RCV000486339 SCV000571884 uncertain significance not provided 2017-06-27 criteria provided, single submitter clinical testing This variant is denoted TP53 c.634T>A at the cDNA level, p.Phe212Ile (F212I) at the protein level, and results in the change of a Phenylalanine to an Isoleucine (TTT>ATT). This variant was observed in association with adrenocortical carcinoma, and functional analysis revealed decreased transcriptional activation (Wasserman 2015). In addition, this variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Phe212Ile was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Phenylalanine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. TP53 Phe212Ile 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 Phe212Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000687495 SCV000815064 uncertain significance Li-Fraumeni syndrome 2018-10-22 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with isoleucine at codon 212 of the TP53 protein (p.Phe212Ile). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and isoleucine. 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: 422414). Experimental studies in yeast and human cells have shown that this variant impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609, 25584008). 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.

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