Submissions for variant NM_000546.6(TP53):c.769C>G (p.Leu257Val)

dbSNP: rs779761818

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001026723	SCV001189160	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-19	criteria provided, single submitter	clinical testing	The p.L257V variant (also known as c.769C>G), located in coding exon 6 of the TP53 gene, results from a C to G substitution at nucleotide position 769. The leucine at codon 257 is replaced by valine, an amino acid with highly similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to exhibit loss of transactivation capacity in yeast based functional studies (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). A separate alteration at this codon (p.L257Q) has been previously reported in an individual with multiple primary tumors whose family satisfied clinical diagnostic criteria for Li-Fraumeni syndrome (Mazoyer S et al. Oncogene. 1994 Apr;9(4):1237-9). This amino acid position is highly conserved in available vertebrate species. In addition, the p.L257V alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV001053924	SCV001218210	uncertain significance	Li-Fraumeni syndrome	2019-11-19	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been reported to affect TP53 protein function (PMID: 12826609). This variant has not been reported in the literature in individuals with TP53-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with valine at codon 257 of the TP53 protein (p.Leu257Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine.
Genome-Nilou Lab	RCV002290559	SCV002581979	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001026723	SCV002582003	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing