Submissions for variant NM_000546.6(TP53):c.709A>G (p.Met237Val)

dbSNP: rs730882004

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 237 of the TP53 protein (p.Met237Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 26681312, 28973705). ClinVar contains an entry for this variant (Variation ID: 182934). 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). 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.
Color Diagnostics, LLC DBA Color Health	RCV001526334	SCV001736648	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-14	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 237 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to be partially functional in yeast transactivation assay (PMID: 12826609, DOI: 10.1182/blood-2019-124622), and non-functional in human cell growth assays and exhibit dominant negative effect (PMID: 29979965, 30224644). This variant and other missense variants occurring at the same codon, p.Met237Lys and p.Met237lIe, showed significantly reduced transcriptional activity in yeast assays (Fischer 2019, dissertation, University of Toronto). This variant has been reported in an individual affected with breast cancer and meeting clinical testing criteria for Li-Fraumeni syndrome (PMID: 26681312) and in an individual affected with early-onset bilateral breast cancer meeting the Chompret criteria for Li-Fraumeni syndrome (PMID: 29875428). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this variant in hereditary cancer conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV001526334	SCV002582014	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288692	SCV002582090	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001526334	SCV002663091	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-02-28	criteria provided, single submitter	clinical testing	The p.M237V variant (also known as c.709A>G), located in coding exon 6 of the TP53 gene, results from an A to G substitution at nucleotide position 709. The methionine at codon 237 is replaced by valine, an amino acid with highly similar properties. The p.M237V variant is in the DNA binding domain of the TP53 protein and is reported to have partially 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). TP53 p.M237V was reported in a woman with bilateral breast cancer at ages 22 and 41 (Turner SA et al. Genet Med, 2019 02;21:426-430). Based on internal structural analysis, p.M237V disrupts important hydrogen bonding interactions and the local structure of a functionally important loop near a zinc-binding motif within the DNA binding site of TP53 (Ambry internal data; Golovenko D et al. Structure. 2018 Sep 4;26(9):1237-1250; Lukman S et al. PLoS One. 2013 Nov 12;8(11); Butler JS and Loh SN. Biochemistry. 2003 Mar 4;42(8):2396-403; Bullock AN, Henckel J, Fersht AR. Oncogene. 2000 Mar 2;19(10):1245-56). This alteration was observed 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel in a patient who met LFS criteria, and has been observed in at least one individual with a personal and/or family history that is consistent with TP53-related disease (Susswein LR et al. Genet Med, 2016 08;18:823-32; Ambry internal data). Another alteration at the same codon, p.M237I (c.711G>A), has been described in a classic Li Fraumeni syndrome (LFS) case (Fortes FP et al. Braz. J. Med. Biol. Res., 2015 Jul;48:610-5). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Database of Curated Mutations (DoCM)	RCV000419726	SCV000508904	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430423	SCV000508905	likely pathogenic	Gastric adenocarcinoma	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