ClinVar Genomic variation as it relates to human health

This variant is denoted TP53 c.797G>A at the cDNA level, p.Gly266Glu (G266E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGA>GAA). This variant has been observed in at least one individual with childhood-onset medulloblastoma and another with personal/family reportedly suggestive of Li-Fraumeni syndrome (Bougeard 2008, Rausch 2012). Functional studies have consistently found that TP53 Gly266Glu is not capable of transactivating typical p53 response elements, leads to a loss of growth suppression activity, and does not exhibit a dominant-negative effect (Campomenosi 2001, Monti 2002, Grochova 2008, Slovackova 2010, Kotler 2018). This variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Gly266Glu was not observed in large population cohorts (Lek 2016). This variant is located in the DNA-binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available information, we consider TP53 Gly266Glu to be a likely pathogenic variant.

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965, 20505364]. This variant is expected to disrupt protein structure [Myriad internal data].

The p.G266E pathogenic mutation (also known as c.797G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 797. The glycine at codon 266 is replaced by glutamic acid, an amino acid with similar properties. This variant has been identified as a somatic mutation in tumors 91 times, and as a germline alteration in one individual with medulloblastoma (Petitjean A et al. IARC TP53 database [version R18, April 2016]. Hum. Mutat. 2007 Jun;28(6):622-9; Kool M et al. Cancer Cell. 2014 Mar; 25(3):393-405). This variant is located in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast based functional studies (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. U.S.A. 2003 Jul 8;100(14):8424-9; Campomenosi P et al. Oncogene. 2001 Jun; 20(27):3573-9). 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; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al. Science 1994 Jul;265(5170):346-55). 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.

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 266 of the TP53 protein (p.Gly266Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 18511570, 24651015; external communication). ClinVar contains an entry for this variant (Variation ID: 161516). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 11429705, 12826609, 12917626, 17724467, 20505364, 29979965, 30224644). This variant disrupts the p.Gly266 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609, 16827139, 20407015, 27523101, 29979965, 30224644; externalcommunication). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

This missense variant replaces glycine with glutamic acid at codon 266 of the TP53 protein. 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 have reported this variant as defective in yeast based transcriptional activation assays, and human cell growth suppression and proliferation assays (PMID: 12826609, 29979965, 30224644). This variant has been reported in individuals affected with childhood-onset medulloblastoma (PMID: 22265402, 24651015), adrenocortical carcinoma (PMID: 26580448, 32371905), and in an individual with a personal and/or family history suggestive of Li Fraumeni syndrome (PMID: 18511570). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

Converted during submission to Uncertain significance.