Submissions for variant NM_000546.5(TP53):c.764T>A (p.Ile255Asn) (rs876659675)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221023	SCV000276382	uncertain significance	Hereditary cancer-predisposing syndrome	2015-06-05	criteria provided, single submitter	clinical testing	The p.I255N variant (also known as c.764T>A), located in coding exon 6 of the TP53 gene, results from a T to A substitution at nucleotide position 764. The isoleucine at codon 255 is replaced by asparagine, an amino acid with dissimilar properties. This alteration has been reported as a somatic mutation 11 times in various tumors, but not as a germline mutation by the IARC TP53 database (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9).This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacityin yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (ChoY,Science1994 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.This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis.Since supporting evidence is limited at this time, the clinical significance of p.I255Nremains unclear.
Invitae	RCV000633370	SCV000754592	uncertain significance	Li-Fraumeni syndrome	2017-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with asparagine at codon 255 of the TP53 protein (p.Ile255Asn). The isoleucine residue is highly conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as a somatic variant in individuals affected with acute myeloid leukemia (PMID: 26781615, 26230955), but has not been reported as a germline variant in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 232289). An experimental study in yeast has shown that this variant impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). A single amino acid deletion at this codon (p.Ile255del) has been reported as a de novo variant in an individual affected with breast cancer, and has been determined to be likely pathogenic (Invitae). Although the single amino acid deletion and the missense change may affect the function of the TP53 protein in different ways, this suggests that this isoleucine residue is critical for TP53 protein function. 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.
Database of Curated Mutations (DoCM)	RCV000433813	SCV000508702	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440110	SCV000508703	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422868	SCV000508704	likely pathogenic	Chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432689	SCV000508705	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441998	SCV000508706	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425285	SCV000508707	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432486	SCV000508708	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only