ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.700T>C (p.Tyr234His) (rs864622237)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492782 SCV000581136 pathogenic Hereditary cancer-predisposing syndrome 2019-05-29 criteria provided, single submitter clinical testing The p.Y234H pathogenic mutation (also known as c.700T>C), located in coding exon 6 of the TP53 gene, results from a T to C substitution at nucleotide position 700. The tyrosine at codon 234 is replaced by histidine, an amino acid with some similar properties. This alteration was confirmed as a de novo alteration in a 10 month old patient with a rhabdomyosarcoma (Ambry internal data), and was reported in an individual with breast cancer at 33 and a leiomyosarcoma at 48 with loss of heterozygosity in the tumor (Mitchell G et al. PLoS ONE 2013 ; 8(7):e69026). This variant is located in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and deficient apoptosis induction (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul; 100(14):8424-9; Smith PD et al. Oncogene 1999 Apr; 18(15):2451-9). 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). Based on internal structural analysis, this variant may result in a decrease in structural stability (Cho Y et al. Science 1994 Jul; 265(5170):346-55). This amino acid position is well conserved in available vertebrate species. Based on the available evidence, p.Y234H is classified as a pathogenic mutation.
Invitae RCV000530551 SCV000629855 pathogenic Li-Fraumeni syndrome 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 234 of the TP53 protein (p.Tyr234His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Li Fraumeni syndrome (PMID: 23894400, Invitae). ClinVar contains an entry for this variant (Variation ID: 376691). Experimental studies have shown that this missense change affects transactivation activity of the TP53 protein, is unable to induce p53-responsive MDM2, and has transforming activity as well as mild gain-of-function activity in vitro (PMID: 10871862, 10229196, 11429705, 8080050, 11896595, 22710932, 9525742, 12826609). This variant disrupts the p.Tyr234 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12695689, 28724667, 26556299, Invitae). 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.
Database of Curated Mutations (DoCM) RCV000427499 SCV000510313 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436907 SCV000510314 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419222 SCV000510315 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426894 SCV000510316 likely pathogenic Adrenocortical carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437128 SCV000510317 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418604 SCV000510318 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428839 SCV000510319 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439967 SCV000510320 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418790 SCV000510321 likely pathogenic Small cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428164 SCV000510322 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438411 SCV000510323 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421640 SCV000510324 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431867 SCV000510325 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441352 SCV000510326 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785304 SCV000923872 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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