ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.521G>A (p.Arg174Lys) (rs1064796681)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478775 SCV000573639 uncertain significance not provided 2017-02-22 criteria provided, single submitter clinical testing This variant is denoted TP53 c.521G>A at the cDNA level, p.Arg174Lys (R174K) at the protein level, and results in the change of an Arginine to a Lysine (AGG>AAG). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in multiple tumor types (Caamano 1993, Bulut 2014, COSMIC). This variant 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 Arg174Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Lysine share similar properties, this is considered a conservative amino acid substitution. TP53 Arg174Lys occurs at a position where amino acids with properties similar to Arginine are tolerated across species 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 Arg174Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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