Submissions for variant NM_000546.6(TP53):c.842A>G (p.Asp281Gly)

dbSNP: rs587781525

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129516	SCV000184291	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-11	criteria provided, single submitter	clinical testing	The p.D281G pathogenic mutation (also known as c.842A>G), located in coding exon 7 of the TP53 gene, results from an A to G substitution at nucleotide position 842. The aspartic acid at codon 281 is replaced by glycine, an amino acid with similar properties. This alteration has been reported as presumed de novo in a one year old child with choroid plexus carcinoma whose parents tested negative (Krutilkova V et al. Eur J Cancer, 2005 Jul;41:1597-603). 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 (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Invitae	RCV000633367	SCV000754589	pathogenic	Li-Fraumeni syndrome	2021-04-26	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with glycine at codon 281 of the TP53 protein (p.Asp281Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. For these reasons, this variant has been classified as Pathogenic. Different missense substitutions at this codon (p.Asp281Asn, p.Asp281Tyr, p.Asp281Val, p.Asp281Ala, p.Asp281Glu, p.Asp281His) have been reported in individuals with TP53-related cancers (PMID: 17572079, 25293557, 10864200, 17390010, 21305319, 23894400). This suggests that the aspartic acid residue may be critical for TP53 protein function, and that missense substitutions at this position may be pathogenic. Experimental studies have shown that this missense change disrupts the transcriptional transactivation function of the TP53 protein (PMID: 21343334, 12826609, 10064694). This variant has been reported to be de novo in an individual affected with choroid plexus carcinoma (PMID: 15925506). ClinVar contains an entry for this variant (Variation ID: 141141). This variant is not present in population databases (ExAC no frequency).
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237737	SCV002011126	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288626	SCV002581506	pathogenic	Li-Fraumeni syndrome 1	2021-08-02	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000129516	SCV002582450	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288626	SCV002583112	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000633367	SCV005045783	pathogenic	Li-Fraumeni syndrome	2024-01-12	criteria provided, single submitter	clinical testing
Database of Curated Mutations (DoCM)	RCV000434395	SCV000507978	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442813	SCV000507979	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426980	SCV000507980	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436807	SCV000507981	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442068	SCV000507982	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425885	SCV000507983	likely pathogenic	Neuroblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436592	SCV000507984	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418481	SCV000507985	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429146	SCV000507986	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435472	SCV000507987	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418257	SCV000507988	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428043	SCV000507989	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438583	SCV000507990	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423959	SCV000507991	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431187	SCV000507992	likely pathogenic	Papillary renal cell carcinoma type 1	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441016	SCV000507993	likely pathogenic	B-cell chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423760	SCV000507994	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433596	SCV000507995	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only