Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000492273 | SCV000581097 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-09-12 | criteria provided, single submitter | clinical testing | The p.R267P pathogenic mutation (also known as c.800G>C), located in coding exon 7 of the TP53 gene, results from a G to C substitution at nucleotide position 800. The arginine at codon 267 is replaced by proline, an amino acid with dissimilar properties. This variant has been reported in multiple BRCA1/2-negative breast cancer patients (Hauke J et al. Cancer Med. 2018 04;7:1349-1358; Grill S et al. Arch Gynecol Obstet. 2021 06;303:1557-1567). This variant has also been reported in the germline of one female patient diagnosed with an adrenocortical carcinoma at age 1 and then diagnosed with ALL at age 12 (Winter G et al. Leukemia. 2021 05;35:1475-1479). 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). Another alteration at the same codon, p.R267W (c.799C>T), has been reported in several patients meeting either classic Li-Fraumeni syndrome (LFS) criteria or Chompret criteria (Melhem-Bertrandt A et al. Cancer 2012 Feb;118(4):908-13; Stoltze U et al. PLoS ONE, 2018 Jan;13:e0190050; Llovet P et al. Fam. Cancer. 2017 Oct;16(4):567-575; AlHarbi M et al. NPJ Genom Med. 2018 Dec 19;3:35). Yet another alteration at this same position, p.R267Q, has been described in a non-classical Li-Fraumeni syndrome (LFS) family as well as in a child with multiple tumors from an LFS family who was found to harbor three TP53 alterations: R156H, R267Q, and R290H (Prosser et al. Br J Cancer. 1992 Apr;65(4):527-8; Quesnel et al. Oncogene. 1999 Jul 8;18(27):3970-8). The p.R267P variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Invitae | RCV000691629 | SCV000819415 | uncertain significance | Li-Fraumeni syndrome | 2019-06-28 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Arg267 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21761402, 27501770, 28573494, 29324801, 30588330, 16861262, 24076587, 12826609). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant is not present in population databases (ExAC no frequency). 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. An experimental study in yeast has shown that this variant impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). In addition, experimental studies using a lung cancer cell line that carries this variant demonstrates elevated Axl expression and enhanced cell growth, while p21 promoter activity appears unaffected (PMID: 23264849, 22989750). This variant has not been reported as a germline variant in individuals affected with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 428867). This sequence change replaces arginine with proline at codon 267 of the TP53 protein (p.Arg267Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. |
| Ayesha Lab, |
RCV003326137 | SCV004032447 | likely pathogenic | Acute myeloid leukemia | no assertion criteria provided | clinical testing |