ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.856G>A (p.Glu286Lys) (rs786201059)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162466 SCV000212829 pathogenic Hereditary cancer-predisposing syndrome 2014-09-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family
Database of Curated Mutations (DoCM) RCV000422231 SCV000508014 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432936 SCV000508015 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439250 SCV000508016 likely pathogenic Small cell lung cancer 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421987 SCV000508017 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431848 SCV000508018 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443333 SCV000508019 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424388 SCV000508020 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431629 SCV000508021 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443492 SCV000508022 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427820 SCV000508023 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437639 SCV000508024 likely pathogenic Neoplasm of the breast 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420427 SCV000508025 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426778 SCV000508026 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437453 SCV000508027 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419251 SCV000508028 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
GeneDx RCV000255724 SCV000322468 pathogenic not provided 2018-08-22 criteria provided, single submitter clinical testing This variant is denoted TP53 c.856G>A at the cDNA level, p.Glu286Lys (E286K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). TP53 Glu286Lys was observed in two affected individuals from a Li-Fraumeni-like family and was also identified in an individual with osteosarcoma (Trkova 2007, Mirabello 2015). 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), and has also been shown to result in loss of growth suppression activity (Kotler 2018). Other functional assays have also demonstrated transactivation activity, but no dominant-negative effect over wild-type p53 (Inga 1997, Campomenosi 2001, Monti 2002, Monti 2003, Pavlova 2003, Grochova 2008, Hassan 2008). TP53 Glu286Lys 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 evidence, we consider TP53 Glu286Lys to be pathogenic.
Genome Sciences Centre,British Columbia Cancer Agency RCV000506006 SCV000598653 likely pathogenic Vulvar adenocarcinoma of mammary gland type no assertion criteria provided research
Invitae RCV000466372 SCV000545283 pathogenic Li-Fraumeni syndrome 2017-08-08 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 286 of the TP53 protein (p.Glu286Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two individuals from a family affected with Li-Fraumeni-like syndrome and in an individual affected with osteosarcoma (PMID: 17567834, 25896519). ClinVar contains an entry for this variant (Variation ID: 183752). This variant is located within the DNA binding domain of the TP53 protein (PMID: 17311302). Experimental studies using yeast-based functional assays have shown that this variant affects TP53 protein conformation and disrupts TP53 transactivation activity  (PMID: 12826609, 17724467). A different missense substitution at this codon (p.Glu286Ala) has been determined to be likely pathogenic (PMID: 1569604, 17606709, 20128691, 12826609). This suggests that the glutamic acid residue is critical for TP53 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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