Submissions for variant NM_000546.6(TP53):c.856G>A (p.Glu286Lys)

dbSNP: rs786201059

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162466	SCV000212829	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-28	criteria provided, single submitter	clinical testing	The p.E286K pathogenic mutation (also known as c.856G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 856. The glutamic acid at codon 286 is replaced by lysine, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This alteration has been detected in a Li-Fraumeni-like (LFL) family in a father-son pair; the father was diagnosed with thyroid cancer at age 18y and the son was diagnosed with rhabdomyosarcoma and Burkitt lymphoma at ages 3y and 7y, respectively (Trkova M et al. Cancer. 2007; 110:694-702). Another disease-causing mutation at the same codon, p.E286A, has also been described in published literature in a family with Li-Fraumeni syndrome (LFS). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000255724	SCV000322468	pathogenic	not provided	2021-06-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11590071, 9635858, 12970738, 26425688, 27101868, 23009112, 17646286, 18843282, 11429705, 11023613, 29416795, 25896519, 8316628, 17294448, 17417968, 30443844, 17567834, 24077944, 9364015, 18242117, 22768918, 12067251, 7731702, 10767639, 25408419, 24224046, 11896595, 24113472, 15037740, 12917626, 12792784, 17724467, 20505364, 18555592, 15580553, 9581814, 14559903, 28160562, 21810023, 26900293, 23531339, 25196205, 11051239, 28980058, 29077256, 22575263, 24927749, 28973495, 29700339, 29885407, 29099487, 29946497, 29979965, 30720243, 30840781, 27535533, 15510160, 30224644)
Invitae	RCV000466372	SCV000545283	pathogenic	Li-Fraumeni syndrome	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 286 of the TP53 protein (p.Glu286Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) 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). 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: 12826609, 17311302, 17724467, 29979965, 30224644). This variant disrupts the p.Glu286 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1569604, 12826609, 17606709, 20128691). 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.
Genome-Nilou Lab	RCV000162466	SCV002582448	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288710	SCV002583109	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288710	SCV004931102	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-21	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 15037740, 20505364, 17724467]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 17567834, 28772286].
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 carcinoma	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	Breast neoplasm	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	Gastric adenocarcinoma	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
Genome Sciences Centre, British Columbia Cancer Agency	RCV000506006	SCV000598653	likely pathogenic	Vulvar adenocarcinoma of mammary gland type		no assertion criteria provided	research