ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.842A>G (p.Asp281Gly) (rs587781525)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129516 SCV000184291 pathogenic Hereditary cancer-predisposing syndrome 2014-01-13 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,Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
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 Neoplasm of the breast 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 Adenocarcinoma of stomach 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 Renal cell carcinoma, papillary, 1 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441016 SCV000507993 likely pathogenic 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
Invitae RCV000633367 SCV000754589 pathogenic Li-Fraumeni syndrome 2018-05-03 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. This variant is not present in population databases (ExAC no frequency). 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). Experimental studies have shown that this missense change disrupts the transcriptional transactivation function of the TP53 protein (PMID: 21343334, 12826609, 10064694). 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. For these reasons, this variant has been classified as Pathogenic.

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