Total submissions: 16
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000809457 | SCV000949608 | uncertain significance | Li-Fraumeni syndrome | 2019-05-01 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine with asparagine at codon 234 of the TP53 protein (p.Tyr234Asn). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in the germline of individuals with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 376692). This variant has been reported to affect TP53 protein function (PMID: 12826609, 19850740, 12509279). This variant disrupts the p.Tyr234 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (PMID: 23894400, 12695689, 28724667, Invitae), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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 | RCV001025925 | SCV001188207 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-05-23 | criteria provided, single submitter | clinical testing | The p.Y234N variant (also known as c.700T>A), located in coding exon 6 of the TP53 gene, results from a T to A substitution at nucleotide position 700. The tyrosine at codon 234 is replaced by asparagine, an amino acid with dissimilar 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). Additional 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). While this exact alteration has not been reported in the literature, three other alterations at this codon (p.Y234H, p.Y234C, and p.Y234D) have been reported in individuals meeting either classic Li-Fraumeni syndrome criteria or Chompret criteria (Pepper C et al. Cell Cycle. 2003 Jan-Feb;2(1):53-8); Mitchell G et al. PLoS ONE 2013; 8(7):e69026; Ambry internal data). Based on internal structural assessment, this alteration disrupts the structure of the DNA binding domain (Cho Y et al. Science 1994 Jul;265(5170):346-55). 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 majority of available evidence to date, this variant is likely to be pathogenic. |
Database of Curated Mutations |
RCV000423653 | SCV000510327 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000434769 | SCV000510328 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444893 | SCV000510329 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426512 | SCV000510330 | likely pathogenic | Adenocarcinoma of prostate | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000433276 | SCV000510331 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444101 | SCV000510332 | likely pathogenic | Small cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426723 | SCV000510333 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436114 | SCV000510334 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000418444 | SCV000510335 | likely pathogenic | Adrenocortical carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426109 | SCV000510336 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436336 | SCV000510337 | likely pathogenic | Ovarian Serous Cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000417830 | SCV000510338 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000428072 | SCV000510339 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439167 | SCV000510340 | likely pathogenic | Adenocarcinoma of stomach | 2016-05-31 | no assertion criteria provided | literature only |