Submissions for variant NM_000546.6(TP53):c.1000G>T (p.Gly334Trp)

dbSNP: rs730882028

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492343	SCV000581109	likely pathogenic	Hereditary cancer-predisposing syndrome	2013-08-13	criteria provided, single submitter	clinical testing	​The p.G334W variant (also known as c.1000G>T) is located in coding exon 9 of the TP53 gene. This alteration results from a G to T substitution at nucleotide position 1000. The glycine at codon 334 is replaced by tryptophan, an amino acid with highly dissimilar properties. This variant was detected in one Korean individual's non-small cell lung cancer tumor sample along with another TP53 mutation (Lee et al. J Korean Med Sci. 2010. 25:698-705). The p.G334W alteration is located in the tetramerization domain of the protein which is critical in tumor suppressor activity. Another alteration at codon 334 (p.G334V) showed lower DNA binding activity and transactivation ability in thermal stability studies (Kamada et al. J Biological Chem. 2011 Jan; 286(1):252-258). This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. Based on protein sequence alignment, 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 majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000492343	SCV000912009	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-10-05	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with tryptophan at codon 334 in the tetramerization domain of the TP53 protein and is located 7 nucleotides from the intron 9 splice acceptor site. This variant alters the conserved glycine residue that connects a short beta-strand (Glu326-Arg333) and an alpha-helix (Arg335-Gly356) of each subunit of the tetramer by facilitating a sharp turn (PMID: 20516128, 26572807). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies performed in yeast assays and ex vivo cultured cells have shown that this variant has largely neutral effect on the tetramer formation and transactivation function of the TP53 protein (PMID: 12826609, 16007150, 19454241) and does not exhibit dominant negative effect or loss of TP53 function in a human cell growth suppression assay (PMID: 30224644). This variant has been observed to segregate with breast cancer, glioblastoma brain cancer, esophageal and rectal cancer in a family affected with Li-Fraumeni syndrome (Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Gly334Arg, has been observed in multiple families affected with Li-Fraumeni syndrome meeting Chompret criteria (PMID: 23580068, 25503501, 25584008, 32675277; ClinVar variation ID: 182969) with reported incomplete penetrance (PMID: 25584008, 32675277), indicating that glycine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Genome-Nilou Lab	RCV000492343	SCV002582337	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289665	SCV002582998	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing