Submissions for variant NM_000546.6(TP53):c.559G>C (p.Gly187Arg)

dbSNP: rs776167460

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001302589	SCV001491803	uncertain significance	Li-Fraumeni syndrome	2020-06-14	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with arginine at codon 187 of the TP53 protein (p.Gly187Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 5 of the TP53 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Li Fraumeni syndrome (PMID: 30239254). ClinVar contains an entry for this variant (Variation ID: 635392). This variant has been reported not to substantially affect TP53 protein function (PMID: 12826609, 29979965, 30224644). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Ambry Genetics	RCV002343642	SCV002651396	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-10-23	criteria provided, single submitter	clinical testing	The c.559G>C variant (also known as p.G187R), located in coding exon 4 of the TP53 gene, results from a G to C substitution at nucleotide position 559. This change occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the glycine at codon 187 to arginine, an amino acid with dissimilar properties. This alteration was reported in multiple generations of a family meeting Chompret criteria (Doyle MR et al. Pediatr Hematol Oncol, 2018 Apr;35:203-207). This variant is in the DNA binding domain of the TP53 protein and is reported to have transactivation similar to wild type in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9), and 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), however, these assays do not measure the impact of potential splice defects. This nucleotide position is highly conserved in available vertebrate species, and this amino acid position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice donor site. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV000786835	SCV000925729	not provided	not provided		no assertion provided	in vitro
Hereditary Cancer Clinic, Medical College of Georgia	RCV002292581	SCV002584908	pathogenic	Li-Fraumeni syndrome 1	2022-07-12	no assertion criteria provided	clinical testing	PP3: Variant is predicted splicing: scSNV-ADA = 0.999973 is greater than 0.999925, and LOF in gene TP53 is known to cause disease (gene has 620 reported pathogenic LOF variants), furthermore BayesDel_addAF = 0.296 is between 0.22 and 0.421 ⇒ moderate pathogenic. PM1: Hot-spot of length 17 amino-acids has 52 missense/in-frame variants (10 pathogenic variants, 42 uncertain variants and no benign), which qualifies as supporting pathogenic. PM2: Variant not found in gnomAD genomes, good gnomAD genomes coverage = 32.5.