Submissions for variant NM_000546.6(TP53):c.746G>A (p.Arg249Lys)

dbSNP: rs587782329

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131246	SCV000186204	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-27	criteria provided, single submitter	clinical testing	The p.R249K pathogenic mutation (also known as c.746G>A), located in coding exon 6 of the TP53 gene, results from a G to A substitution at nucleotide position 746. The arginine at codon 249 is replaced by lysine, an amino acid with highly similar properties. This alteration was reported in one child with adrenal cortical carcinoma (Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast based functional assays (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Eurofins Ntd Llc (ga)	RCV000724753	SCV000232077	uncertain significance	not provided	2015-04-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000724753	SCV000567602	uncertain significance	not provided	2015-08-06	criteria provided, single submitter	clinical testing	This variant is denoted TP53 c.746G>A at the cDNA level, p.Arg249Lys (R249K) at the protein level, and results in the change of an Arginine to a Lysine (AGG>AAG). This variant has not, to our knowledge, been published in the literature as a germline variant; however, TP53 Arg249Lys has been reported as a somatic variant in multiple different tumor types (Cosmic, IARC TP53 Database). TP53 Arg249Lys has also been reported as having non-functional transactivation activity in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003) and demonstrated reduced transcriptional activity in a yeast functional assay (Van der Vorst 2012). TP53 Arg249Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Lysine share similar properties, this is considered a conservative amino acid substitution. TP53 Arg249Lys occurs at a position that is conserved across species and is located in the region of interaction with CCAR2, HIPK1, and ZNF385A (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether TP53 Arg249Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857457	SCV002259639	uncertain significance	Li-Fraumeni syndrome	2023-03-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 249 of the TP53 protein (p.Arg249Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast or ovarian cancer (PMID: 26786923, 30546832). ClinVar contains an entry for this variant (Variation ID: 142241). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965). 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.
Genome-Nilou Lab	RCV000131246	SCV002582008	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288647	SCV002582035	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing