Submissions for variant NM_000546.6(TP53):c.797G>A (p.Gly266Glu)

dbSNP: rs193920774

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255749	SCV000322130	likely pathogenic	not provided	2019-01-07	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV000492556	SCV000581084	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-21	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000709403	SCV000931773	pathogenic	Li-Fraumeni syndrome	2023-02-22	criteria provided, single submitter	clinical testing	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.
Mendelics	RCV000421625	SCV001140251	likely pathogenic	Squamous cell carcinoma of the head and neck	2019-05-28	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000492556	SCV002582355	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288661	SCV002583016	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000709403	SCV004840289	likely pathogenic	Li-Fraumeni syndrome	2023-12-18	criteria provided, single submitter	clinical testing	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.
Myriad Genetics, Inc.	RCV002288661	SCV004931862	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-20	criteria provided, single submitter	clinical testing	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].
Science for Life laboratory, Karolinska Institutet	RCV000149050	SCV000088692	unknown	Malignant tumor of prostate		no assertion criteria provided	not provided	Converted during submission to Uncertain significance.
Database of Curated Mutations (DoCM)	RCV000418979	SCV000508297	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429269	SCV000508298	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436020	SCV000508299	likely pathogenic	B-cell chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418383	SCV000508300	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430374	SCV000508301	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440516	SCV000508302	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422957	SCV000508303	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429720	SCV000508304	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441726	SCV000508305	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423995	SCV000508306	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434273	SCV000508307	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445061	SCV000508308	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421625	SCV000508309	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431935	SCV000508310	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444063	SCV000508311	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424505	SCV000508312	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433054	SCV000508313	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444033	SCV000508314	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785456	SCV000924028	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research