Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000221023 | SCV000276382 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-06-05 | criteria provided, single submitter | clinical testing | The p.I255N variant (also known as c.764T>A), located in coding exon 6 of the TP53 gene, results from a T to A substitution at nucleotide position 764. The isoleucine at codon 255 is replaced by asparagine, an amino acid with dissimilar properties. This alteration has been reported as a somatic mutation 11 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 capacityin yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (ChoY,Science1994 Jul; 265(5170):346-55).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. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 125000 alleles tested) in our clinical cohort.This amino acid position is well 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 p.I255Nremains unclear. |
Invitae | RCV000633370 | SCV000754592 | uncertain significance | Li-Fraumeni syndrome | 2017-12-12 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine with asparagine at codon 255 of the TP53 protein (p.Ile255Asn). The isoleucine residue is highly conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as a somatic variant in individuals affected with acute myeloid leukemia (PMID: 26781615, 26230955), but has not been reported as a germline variant in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 232289). An experimental study in yeast has shown that this variant impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). A single amino acid deletion at this codon (p.Ile255del) has been reported as a de novo variant in an individual affected with breast cancer, and has been determined to be likely pathogenic (Invitae). Although the single amino acid deletion and the missense change may affect the function of the TP53 protein in different ways, this suggests that this isoleucine residue is critical for TP53 protein function. 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. |
Database of Curated Mutations |
RCV000433813 | SCV000508702 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440110 | SCV000508703 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000422868 | SCV000508704 | likely pathogenic | Chronic lymphocytic leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432689 | SCV000508705 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000441998 | SCV000508706 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425285 | SCV000508707 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432486 | SCV000508708 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only |