Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001371092 | SCV001567646 | uncertain significance | Li-Fraumeni syndrome | 2020-03-14 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with leucine at codon 213 of the TP53 protein (p.Arg213Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 376650). This variant has been reported to affect TP53 protein function (PMID: 12826609, 21514416). This variant disrupts the p.Arg213 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17541742, 16736287, 20505364, 16861262, 17724467, 12826609). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |
| Myriad Genetics, |
RCV004022236 | SCV004931617 | likely pathogenic | Li-Fraumeni syndrome 1 | 2024-02-15 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. |
| Ambry Genetics | RCV004948280 | SCV005522069 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-10-30 | criteria provided, single submitter | clinical testing | The p.R213L pathogenic mutation (also known as c.638G>T), located in coding exon 5 of the TP53 gene, results from a G to T substitution at nucleotide position 638. The arginine at codon 213 is replaced by leucine, an amino acid with dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). Another variant at the same codon, p.R213Q c.638G>A, has been described in individuals with clinical histories consistent with Li-Fraumeni syndrome (LFS) (Achatz MI et al. Cancer Lett. 2007 Jan 8;245(1-2):96-102; Arcand SL et al. Breast Cancer Res Treat. 2008 Apr;108(3):399-408; Becherini et al. Neuropathol. Appl. Neurobiol. 2008 Oct;34(5):564-8); Pinto C et al. Fam. Cancer. 2009 May;8(4):383-90; Ruijs MW et al. J. Med. Genet. 2010 Jun;47(6):421-8; Desmond A et al. JAMA Oncol. 2015 Oct;1(7):943-51). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. |