Total submissions: 16
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000204217 | SCV000259812 | uncertain significance | Li-Fraumeni syndrome | 2015-08-07 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine with aspartic acid at codon 234 of the TP53 protein (p.Tyr234Asp). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and aspartic acid. This variant is not present in population databases and has been reported in the literature. This variant was reported in an individual affected with chronic lymphocytic leukemia (PMID: 21232794). It has also been reported in the tumor of a patient with colorectal cancer (PMID: 22982087). Experimental studies in vitro have shown that this missense change may lead to defective transactivation (PMID: 21232794). Other missense mutations, p.Tyr234Cys and p.Tyr234His, have been reported at the same codon in individuals affected with Li-Fraumeni syndrome as well as other isolated cancers (PMID: 12695689, 17606709, 23894400). Experimental studies of these missense mutations suggest that this amino acid may be essential for protein function (PMID: 9290701, 21232794, 21343334). In summary, clinical and experimental evidence suggests that other missense mutations at this position may lead to disrupted protein function. However, evidence directly related this p.Tyr234Asp variant is limited. For these reasons, this change has been classified as a Variant of Uncertain Significance. |
Ambry Genetics | RCV000492197 | SCV000581114 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2016-03-18 | criteria provided, single submitter | clinical testing | The p.Y234D variant (also known as c.700T>G), located in coding exon 6 of the TP53 gene, results from a T to G substitution at nucleotide position 700. The tyrosine at codon 234 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This variantwas detected in an individual meeting clinical criteria forclassicLi-Fraumenisyndrome(Ambryinternal data).This variant is in the DNA binding domain of theTP53protein and is reported to have loss oftransactivationcapacity and predicted toaffectseveral p53isoforms. (IARCTP53database; Kato S et al.ProcNatlAcadSci USA. 2003 Jul 8;100(14):8424-9).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 250000alleles 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. However, based on internal structural analysis, this variant may result in a decrease in structural stability (Cho Y et al.Science1994 Jul; 265(5170):346-55).Additionally, adifferent alterationat the samecodon,p.Y234H, hasbeenreportedin an individual with breast cancer at age 33 and aleiomyosarcomaat age 48,with loss ofheterozygositypresentin the tumor (Mitchell G et al.PLoSONE2013 ; 8(7):e69026).Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
Database of Curated Mutations |
RCV000418073 | SCV000510341 | likely pathogenic | Adenocarcinoma of prostate | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000430896 | SCV000510342 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000441597 | SCV000510343 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000424345 | SCV000510344 | likely pathogenic | Adenocarcinoma of stomach | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000433328 | SCV000510345 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440475 | SCV000510346 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423238 | SCV000510347 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000433956 | SCV000510348 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000445176 | SCV000510349 | likely pathogenic | Ovarian Serous Cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425587 | SCV000510350 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432845 | SCV000510351 | likely pathogenic | Small cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000445265 | SCV000510352 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000424462 | SCV000510353 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000435222 | SCV000510354 | likely pathogenic | Adrenocortical carcinoma | 2016-05-31 | no assertion criteria provided | literature only |