ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.700T>A (p.Tyr234Asn) (rs864622237)

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Total submissions: 16
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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 (DoCM) RCV000423653 SCV000510327 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434769 SCV000510328 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444893 SCV000510329 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426512 SCV000510330 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433276 SCV000510331 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444101 SCV000510332 likely pathogenic Small cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426723 SCV000510333 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) 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 (DoCM) RCV000418444 SCV000510335 likely pathogenic Adrenocortical carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426109 SCV000510336 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436336 SCV000510337 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417830 SCV000510338 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428072 SCV000510339 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439167 SCV000510340 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only

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