Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000492567 | SCV000581147 | uncertain significance | Hereditary cancer-predisposing syndrome | 2016-10-12 | criteria provided, single submitter | clinical testing | The p.S215R variant (also known as c.643A>C), located in coding exon 5 of the TP53 gene, results from an A to C substitution at nucleotide position 643. The serine at codon 215 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported as a somatic mutation 5 times in various tumors, but not as a germline mutation by the IARC TP53 database (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast based functional studies (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). This codon has also been identified as a critical phosphorylation site; when phosphorylated, it abrogates p53 DNA binding and transactivation activity (Liu Q, J. Biol. Chem. 2004 Dec; 279(50):52175-82). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. |
| Labcorp Genetics |
RCV002523445 | SCV003317129 | likely pathogenic | Li-Fraumeni syndrome | 2023-01-04 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ser215 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 428895). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 32817165). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 215 of the TP53 protein (p.Ser215Arg). |
| Myriad Genetics, |
RCV004023282 | SCV004933436 | 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]. |