ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.709A>G (p.Met237Val) (rs730882004)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Database of Curated Mutations (DoCM) RCV000419726 SCV000508904 likely pathogenic Neoplasm of the breast 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430423 SCV000508905 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439317 SCV000508906 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422107 SCV000508907 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429307 SCV000508908 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439996 SCV000508909 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421083 SCV000508910 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431774 SCV000508911 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443569 SCV000508912 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421733 SCV000508913 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434187 SCV000508914 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443583 SCV000508915 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
GeneDx RCV000161033 SCV000211755 uncertain significance not specified 2017-03-02 criteria provided, single submitter clinical testing This variant is denoted TP53 c.709A>G at the cDNA level, p.Met237Val (M237V) at the protein level,and results in the change of a Methionine to a Valine (ATG>GTG). This variant has been reported as a somatic variantin multiple cancer types including breast, colon and lung (Vega 1997, Deissler 2004, Malhotra 2013). Although anothervariant at this residue, TP53 Met237Ile, has been shown to severely impact transactivation in yeast-based assays(Kato 2003, Dearth 2007, Monti 2011), TP53 Met237Val is reported as having partially functional transactivation in theInternational Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53Met237Val was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBIExome Sequencing Project). Since Methionine and Valine share similar properties, this is considered a conservativeamino acid substitution. TP53 Met237Val occurs at a position that is conserved across species and is located in theDNA-binding domain (Bode 2004). In silico analyses predict that this variant is probably damaging to protein structureand function. Based on currently available evidence, it is unclear whether TP53 Met237Val is a pathogenic or benignvariant. We consider it to be a variant of uncertain significance.
Invitae RCV000200500 SCV000254637 uncertain significance Li-Fraumeni syndrome 2018-08-31 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 237 of the TP53 protein (p.Met237Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 182934). Experimental studies of transactivation activity in yeast indicate that this missense change is partially functional (PMID: 12826609). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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