ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.587G>A (p.Arg196Gln) (rs483352697)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000196467 SCV000254632 uncertain significance Li-Fraumeni syndrome 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 196 of the TP53 protein (p.Arg196Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with chronic lymphocytic leukemia (PMID: 28476805). This variant has been reported in individuals in the Universal Mutation Database (PMID: 10612827). ClinVar contains an entry for this variant (Variation ID: 216467). Experimental studies have shown that this missense change has a partial impact on the transcriptional transactivation activity of the TP53 protein (PMID: 12826609, 15781620, 12917626). However, the clinical significance of these findings is uncertain. 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 RCV000235733 SCV000292696 uncertain significance not provided 2017-09-13 criteria provided, single submitter clinical testing This variant is denoted TP53 c.587G>A at the cDNA level, p.Arg196Gln (R196Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant was reportedly observed in the germline of a patient with aplastic anemia (Keel 2016). TP53 Arg196Gln is reported as having partially functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003) and additional transactivation assays did not find this variant to cause a dominant-negative effect (Marutani 1999, Monti 2003). TP53 Arg196Gln was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. TP53 Arg196Gln occurs at a position that is conserved across species and is located in the DNA Binding 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 Arg196Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000580263 SCV000686754 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing

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