ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.517G>A (p.Val173Met) (rs876660754)

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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 RCV000214341 SCV000278424 likely pathogenic Hereditary cancer-predisposing syndrome 2015-09-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification
Database of Curated Mutations (DoCM) RCV000435365 SCV000509876 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418173 SCV000509877 likely pathogenic Neoplasm of the breast 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424469 SCV000509878 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435180 SCV000509879 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418817 SCV000509880 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429546 SCV000509881 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439338 SCV000509882 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418768 SCV000509883 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429913 SCV000509884 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440133 SCV000509885 likely pathogenic Small cell lung cancer 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423333 SCV000509886 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433605 SCV000509887 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441217 SCV000509888 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423542 SCV000509889 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434638 SCV000509890 likely pathogenic Adrenocortical carcinoma 2016-05-31 no assertion criteria provided literature only
GeneDx RCV000223396 SCV000279617 pathogenic not provided 2018-05-25 criteria provided, single submitter clinical testing This variant is denoted TP53 c.517G>A at the cDNA level, p.Val173Met (V173M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant was observed in a family that met clinical diagnostic criteria for Li Fraumeni syndrome (Achatz 2007). Multiple tansactivation and apoptosis activity assays demonstrate loss of TP53 function (Marutani 1999, Baroni 2004, Dearch 2007, Golubovskaya 2008, Monti 2011). TP53 Val173Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. TP53 Val173Met occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located in the DNA binding domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider TP53 Val173Met to be a pathogenic variant.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785308 SCV000923876 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Invitae RCV000477355 SCV000545293 pathogenic Li-Fraumeni syndrome 2018-04-08 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 173 of the TP53 protein (p.Val173Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with soft tissue sarcoma and breast cancer. Although the family had a history of Li-Fraumeni tumors, segregation studies were not reported for this variant (PMID: 16494995). This variant has also been observed to be de novo in an individual affected with both osteosarcoma and breast cancer at a young age (Invitae). ClinVar contains an entry for this variant (Variation ID: 233951). Experimental studies have shown that this missense change disrupts the transcriptional transactivation function of the TP53 protein (PMID: 21343334, 12826609). For these reasons, this variant has been classified as Pathogenic.

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