ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.559G>A (p.Gly187Ser)

gnomAD frequency: 0.00001  dbSNP: rs776167460
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001042375 SCV001206053 uncertain significance Li-Fraumeni syndrome 2021-06-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 187 of the TP53 protein (p.Gly187Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have shown that this variant does not substantially affect TP53 protein function (PMID: 12826609,30224644,29979965 ). This variant has not been reported in the literature in individuals with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 840399). This variant is present in population databases (rs776167460, ExAC 0.001%).
Ambry Genetics RCV002348357 SCV002648850 uncertain significance Hereditary cancer-predisposing syndrome 2021-07-23 criteria provided, single submitter clinical testing The c.559G>A variant (also known as p.G187S), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 559. The amino acid change results in glycine to serine at codon 187, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing; however direct evidence is insufficient at this time (Ambry internal data). This alteration has been reported as a variant of unknown significance identified via whole exome sequencing on samples from childhood cancer survivors; however clinical history was not provided for this individual (Wang Z et al. J Clin Oncol, 2018 07;36:2078-2087). One study which performed RNA analysis in various tumors harboring various TP53 variants demonstrated low mRNA levels for this variant; however splicing profiles were not directly assessed (Carbonnier V et al. Sci Rep, 2020 11;10:20368). This variant is in the DNA binding domain of the TP53 protein and is reported to have transactivation similar to wildtype in yeast-based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9), and studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387), however, these assays do not measure the impact of potential splice defects. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. This amino acid position is well conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be inconclusive by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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