Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000129637 | SCV000184432 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-06-17 | criteria provided, single submitter | clinical testing | The p.I232T variant (also known as c.695T>C), located in coding exon 6 of the TP53 gene, results from a T to C substitution at nucleotide position 695. The isoleucine at codon 232 is replaced by threonine, an amino acid with some similar properties. This alteration was identified in a family of Dutch origin whom met both revised Chompret criteria, and Li-Fraumeni-like (LFL) syndrome criteria (Ruijs MW et al. J. Med. Genet. 2010 Jun;47:421-8). The p.I232T variant has also been reported in a woman diagnosed with breast cancer at age 23 who was later diagnosed with therapy-developed leukemia at the age of 48 (Churpek JE et al. Cancer. 2016 Jan;122:304-11). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and predicted to affect several p53 isoforms (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Bullock AN et al. Oncogene. 2000 Mar;19:1245-56). Studies conducted in human cell lines indicate this alteration is deficient 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). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Ce |
RCV002510789 | SCV002822355 | pathogenic | not provided | 2022-12-01 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV005089636 | SCV005836492 | pathogenic | Li-Fraumeni syndrome | 2025-01-11 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 232 of the TP53 protein (p.Ile232Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and/or clinical features of Li-Fraumeni syndrome (PMID: 20522432, 26641009). ClinVar contains an entry for this variant (Variation ID: 141224). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. This variant disrupts the p.Ile232 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Mayo Clinic Laboratories, |
RCV000582737 | SCV000692076 | uncertain significance | not specified | no assertion criteria provided | clinical testing |