ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.1135C>A (p.Arg379Ser) (rs749061599)

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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 RCV000166408 SCV000217202 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000236607 SCV000293283 uncertain significance not provided 2016-11-10 criteria provided, single submitter clinical testing This variant is denoted TP53 c.1135C>A at the cDNA level, p.Arg379Ser (R379S) at the protein level, and results in the change of an Arginine to a Serine (CGC>AGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant 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). TP53 Arg379Ser 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 Serine differ in some properties, this is considered a semi-conservative amino acid substitution. TP53 Arg379Ser occurs at a position that is not conserved and is located within the C-terminal regulatory 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 Arg379Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000412389 SCV000489454 uncertain significance Li-Fraumeni syndrome 1 2016-10-06 criteria provided, single submitter clinical testing
Invitae RCV000795303 SCV000934758 uncertain significance Li-Fraumeni syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 379 of the TP53 protein (p.Arg379Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with ovarian cancer (PMID: 27616075). ClinVar contains an entry for this variant (Variation ID: 186762). An experimental study in yeast has shown that this variant partially impairs 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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