Submissions for variant NM_000546.6(TP53):c.869G>T (p.Arg290Leu)

dbSNP: rs55819519

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781912	SCV000920316	uncertain significance	not specified	2024-08-30	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.869G>T (p.Arg290Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251482 control chromosomes. c.869G>T has been reported in the literature in two individuals from the same family affected with Li-Fraumeni Syndrome (e.g., Anensen_2006). These data indicate that the variant may be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, however with conflicting results. One study found no induction of p53 during therapy in patient cells (e.g., Anensen_2006), while other studies have shown that the variant maintains wild-type p53-like anti-proliferative capacity in vitro (e.g., Kotler_2018). The following publications have been ascertained in the context of this evaluation (PMID: 16437140, 35425963, 29979965). ClinVar contains an entry for this variant (Variation ID: 633445). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Ambry Genetics	RCV001018200	SCV001179400	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-14	criteria provided, single submitter	clinical testing	The p.R290L variant (also known as c.869G>T), located in coding exon 7 of the TP53 gene, results from a G to T substitution at nucleotide position 869. The arginine at codon 290 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in a 51-year-old female with a personal history of breast cancer, three soft tissue sarcomas and anal carcinoma, the first sarcoma being diagnosed at the age of 28. This alteration was also reported in the woman's son, who had a rhabdomyosarcoma and died from acute leukemia at age 12 (Anensen N et al. Leukemia, 2006 Apr;20:734-6). This variant is in the DNA binding domain of the TP53 protein and is reported to have functional transactivation in yeast based 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 remains proficient at growth suppression (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 not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001210557	SCV001382051	uncertain significance	Li-Fraumeni syndrome	2020-12-29	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. Experimental studies have shown that this variant does not substantially affect TP53 protein function (PMID: 12826609, 30224644, 29979965). This variant has been observed in individual(s) with clinical features of Li Fraumeni syndrome (PMID: 16437140). ClinVar contains an entry for this variant (Variation ID: 633445). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 290 of the TP53 protein (p.Arg290Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine.
Baylor Genetics	RCV001294068	SCV001482863	uncertain significance	Bone marrow failure syndrome 5	2020-02-23	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].