Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001301950 | SCV001491135 | uncertain significance | Li-Fraumeni syndrome | 2020-06-14 | criteria provided, single submitter | clinical testing | This variant has been reported to affect TP53 protein function (PMID: 12826609, 29979965, 30224644, 30840781). This sequence change replaces isoleucine with phenylalanine at codon 255 of the TP53 protein (p.Ile255Phe). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 376621). This variant disrupts the p.Ile255 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21761402, Invitae). 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. |
Ambry Genetics | RCV002392946 | SCV002670637 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-05-13 | criteria provided, single submitter | clinical testing | The p.I255F variant (also known as c.763A>T), located in coding exon 6 of the TP53 gene, results from an A to T substitution at nucleotide position 763. The isoleucine at codon 255 is replaced by phenylalanine, an amino acid with highly similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration has a dominant negative effect and 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 alteration has been reported in a cohort of individuals diagnosed with breast cancer (Alsner J et al. Clin. Cancer Res. 2000 Oct;6(10):3923-31), and has numerous somatic observations (cancerhotspots.org; IARCTP53 database). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Database of Curated Mutations |
RCV000436676 | SCV000508688 | likely pathogenic | B-cell chronic lymphocytic leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444896 | SCV000508689 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425759 | SCV000508690 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436027 | SCV000508691 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000418615 | SCV000508692 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000428426 | SCV000508693 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000435616 | SCV000508694 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000785451 | SCV000924023 | likely pathogenic | Neoplasm of ovary | 2018-12-01 | no assertion criteria provided | research |