ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.821T>C (p.Val274Ala)

dbSNP: rs1057520006
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Total submissions: 13
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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 (DoCM) RCV000421817 SCV000510035 likely pathogenic Ovarian serous cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432482 SCV000510036 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444136 SCV000510037 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426067 SCV000510038 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433292 SCV000510039 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443517 SCV000510040 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426772 SCV000510041 likely pathogenic Prostate adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437438 SCV000510042 likely pathogenic Small cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420150 SCV000510043 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427353 SCV000510044 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438006 SCV000510045 likely pathogenic Gastric adenocarcinoma 2016-05-31 no assertion criteria provided literature only

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