Total submissions: 13
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001056029 | SCV001220448 | uncertain significance | Li-Fraumeni syndrome | 2020-02-27 | criteria provided, single submitter | clinical testing | 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. This variant has been reported disrupt TP53 protein function (PMID: 12826609, 11313981, 14559903). This variant has not been reported in the literature in individuals with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 376677). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with alanine at codon 247 of the TP53 protein (p.Val274Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. |
Ambry Genetics | RCV002429350 | SCV002678307 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2015-05-29 | criteria provided, single submitter | clinical testing | The p.V274A variant (also known as c.821T>C), located in coding exon 7 of the TP53 gene, results from a T to C substitution at nucleotide position 821. The valine at codon 274 is replaced by alanine, an amino acid with similar properties. Functional analysis has shown that this alteration is temperature sensitive, and loses transactivation capacity and the ability to suppress cell growth at 37 degrees (Shiraishi K et al. J. Biol. Chem. 2004 Jan; 279(1):348-55. Inga A et al. Oncogene 2001 Jan; 20(4):501-13, Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Based on internal structural analysis, this variant is in the secondary shell of both DNA binding and Zn binding, and is anticipated to result in a significant decrease in structural stability (Cho Y et al. Science 1994 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, including one individual with multiple LFS related tumors before the age of 35. This amino acid position is not well 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 |
RCV000421817 | SCV000510035 | likely pathogenic | Ovarian serous cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432482 | SCV000510036 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444136 | SCV000510037 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426067 | SCV000510038 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000433292 | SCV000510039 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000443517 | SCV000510040 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426772 | SCV000510041 | likely pathogenic | Prostate adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437438 | SCV000510042 | likely pathogenic | Small cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000420150 | SCV000510043 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427353 | SCV000510044 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438006 | SCV000510045 | likely pathogenic | Gastric adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only |