ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.221C>T (p.Ala74Val) (rs587781832)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130119 SCV000184950 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000487230 SCV000570633 uncertain significance not provided 2018-12-11 criteria provided, single submitter clinical testing This variant is denoted TP53 c.221C>T at the cDNA level, p.Ala74Val (A74V) at the protein level, and results in the change of an Alanine to a Valine (GCC>GTC). This variant has not, to our knowledge, been published in the literature as either a pathogenic or benign germline variant. This variant is reported as having functional transactivation activity in the International Agency for Research on Cancer (IARC) TP53 database based on functional studies by Kato et al. (2003). TP53 Ala74Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. TP53 Ala74Val is located in the SH3 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 Ala74Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000816275 SCV000956775 uncertain significance Li-Fraumeni syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 74 of the TP53 protein (p.Ala74Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs587781832, ExAC 0.02%). This variant has not been reported as a germline variant in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 141547). An experimental study in yeast has shown that this variant does not impair 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.

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