ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.797G>A (p.Gly266Glu) (rs193920774)

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Total submissions: 25
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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 2019-02-28 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). Based on the available evidence, this alteration is interpreted as a disease-causing mutation.
Mendelics RCV000709403 SCV000839111 likely pathogenic Li-Fraumeni syndrome 2018-07-02 criteria provided, single submitter clinical testing
Invitae RCV000709403 SCV000931773 pathogenic Li-Fraumeni syndrome 2020-07-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 266 of the TP53 protein (p.Gly266Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. 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: 18511570, 24651015, external communication). ClinVar contains an entry for this variant (Variation ID: 161516). This variant has been reported to affect TP53 protein function (PMID: 12826609, 20505364, 11429705, 12917626, 17724467, 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: 27523101, 12826609, 16827139, 20407015, 29979965, 30224644, external communication). 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
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 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 Center Cologne,University Hospital Cologne RCV000785456 SCV000924028 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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