rs55819519
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000546.6(TP53):c.869G>T(p.Arg290Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461890Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727244
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not specified Uncertain:1
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. -
Li-Fraumeni syndrome Uncertain:1
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 290 of the TP53 protein (p.Arg290Leu). This variant is not present in population databases (gnomAD no frequency). This missense change 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). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644). 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. -
Bone marrow failure syndrome 5 Uncertain:1
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Hereditary cancer-predisposing syndrome Uncertain:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at