ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.711G>A (p.Met237Ile) (rs587782664)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV001527088 SCV001737927 pathogenic Li-Fraumeni syndrome 1 2021-04-20 reviewed by expert panel curation This variant has >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). This variant has been reported in 1 proband meeting Classic LFS criteria and 4 probands meeting Chompret criteria (PS4; PMID: 11370630, 25945745, NIH, Invitae, Ambry). This variant was found to co-segregate with disease in multiple affected family members, with 5 or 6 meioses observed (PP1_Moderate; NIH, Invitae). There is one de novo observation in a proband with breast and thyroid cancer in her 30s without parental confirmation (PM6_Supporting; GeneDx). In summary, TP53 c.711G>A (p.Met237Ile) meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM1, PS3, PS4, PP1_Moderate, PM6_Supporting.
Ambry Genetics RCV000132084 SCV000187148 pathogenic Hereditary cancer-predisposing syndrome 2019-09-27 criteria provided, single submitter clinical testing The p.M237I pathogenic mutation (also known as c.711G>A), located in coding exon 6 of the TP53 gene, results from a G to A substitution at nucleotide position 711. The methionine at codon 237 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been reported as a germline alteration in a classic LFS case (Fortes FP et al. Braz. J. Med. Biol. Res. 2015 Jul;48:610-5) as well as in one Li-Fraumeni-like family, and identified in multiple individuals meeting Chompret criteria (Bougeard G et al. J Med Genet. 2001 Apr;38(4):253-7; Ambry Internal Data). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (IARC TP53 database: 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). Several other in vitro studies have shown that the p.M237I alteration is dominant negative and results in a severe deficiency of p53 transactivation activity, causes radio-resistance with increased frequency of spontaneous and radiation-induced mutations and loss of the ability to inhibit DNA synthesis (Monti P et al. Mol Cancer Res. 2011 Mar;9(3):271-9; Dearth LR et al. Carcinogenesis. 2007 Feb;28:289-98; Little JB et al. J Biol Chem. 1995 May12;270(19):11033-6; Vousden KH et al. J Gen Virol. 1993 May;74 (Pt 5):803-10; Wiese C et al. Cancer Res. 2001 Feb 1;61(3):1129-37). Based on internal structural analysis, p.M237I 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000464261 SCV000545260 likely pathogenic Li-Fraumeni syndrome 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 237 of the TP53 protein (p.Met237Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs587782664, ExAC 0.006%). This variant has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 11370630, Invitae). ClinVar contains an entry for this variant (Variation ID: 142714). Experimental studies have shown that this variant affects TP53 protein function (PMID: 12826609, 21343334, 17606709, 29979965, 30224644). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Database of Curated Mutations (DoCM) RCV000435205 SCV000508880 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417987 SCV000508881 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428641 SCV000508882 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441079 SCV000508883 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420354 SCV000508884 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431054 SCV000508885 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441725 SCV000508886 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422710 SCV000508887 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433401 SCV000508888 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440576 SCV000508889 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423376 SCV000508890 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432346 SCV000508891 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Mayo Clinic Laboratories, Mayo Clinic RCV000581940 SCV000692075 uncertain significance not specified no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785336 SCV000923904 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research
CZECANCA consortium RCV001271055 SCV001451874 likely pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing

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