chr17-7673784-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000546.6(TP53):c.836G>A(p.Gly279Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G279R) has been classified 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 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.836G>A | p.Gly279Glu | missense_variant | 8/11 | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.836G>A | p.Gly279Glu | missense_variant | 8/11 | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Li-Fraumeni syndrome 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 20, 2024 | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 16508005]. This variant is expected to disrupt protein structure [Myriad internal data]. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 07, 2019 | Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 8633021, 7718482, 9364015, 11429700, 11429705, 11313981, 16508005, 12909720, 12917626, 29979965, 16861262, 11896595, 30166522, 33504652) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 12, 2022 | The p.G279E pathogenic mutation (also known as c.836G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 836. The glycine at codon 279 is replaced by glutamic acid, an amino acid with a few similar properties. This alteration has been detected in individuals meeting classic Li-Fraumeni diagnostic criteria as well as Chompret criteria (Ambry internal data). This alteration is located in the functionally critical DNA-binding domain. A number of functional assays in both yeast and mammalian cells have shown this alteration to be devoid of transactivation activity, deficient in the induction of apoptosis, and unable to suppress cell growth after UV irradiation (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Menendez D et al. Mol. Cell. Biol. 2006 Mar; 26(6):2297-308; Inga A et al. Oncogene. 2001 Jan; 20(4):501-13; Rokudai Set al. J Biol Chem. 2009 Jan 2;284(1):237-44; Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat Genet. 2018 10;50:1381-1387). Additionally, this variant has been shown to exhibit strong dominant-negative characteristics (Dearth LR et al. Carcinogenesis 2007 Feb; 28(2):289-98; Brachmann RK et al. Proc. Natl. Acad. Sci. U.S.A. 1996 Apr; 93(9):4091-5). Structural analysis indicates that G279 is adjacent to several DNA binding residues, and the p.G279E change creates severe structural perturbations (>15 kcal/mol) resulting in a destabilization of the proper folding of the adjacent loop (Ambry internal analysis). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Ovarian neoplasm Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Squamous cell carcinoma of the head and neck Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not specified Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Li-Fraumeni syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 279 of the TP53 protein (p.Gly279Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with small cell lung cancer (PMID: 33504652). This variant is also known as c.719G>A (G240E). ClinVar contains an entry for this variant (Variation ID: 419454). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 11313981, 11423991, 12826609, 16508005, 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at