ClinVar Miner

Submissions for variant NM_001126112.2(TP53):c.998G>A (p.Arg333His) (rs573154688)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131296 SCV000186268 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-14 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000213064 SCV000211764 uncertain significance not provided 2017-06-21 criteria provided, single submitter clinical testing This variant is denoted TP53 c.998G>A at the cDNA level, p.Arg333His (R333H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant is associated with partial transcriptional activity and retention of the ability to form tetramers (Leroy 2014). However, it 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 Arg333His was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. TP53 Arg333His occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is located in the tetramerization domain (Bode 2004) In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether TP53 Arg333His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000227465 SCV000285219 uncertain significance Li-Fraumeni syndrome 2019-11-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 333 of the TP53 protein (p.Arg333His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs573154688, ExAC 0.006%). This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 142273). An experimental study using a yeast-based functional assay has shown that this missense change does not affect 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.
Color RCV000131296 SCV000686790 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-16 criteria provided, single submitter clinical testing
Counsyl RCV000662455 SCV000784933 uncertain significance Li-Fraumeni syndrome 1 2017-02-07 criteria provided, single submitter clinical testing

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