Submissions for variant NM_000546.6(TP53):c.711G>A (p.Met237Ile)

gnomAD frequency: 0.00001  dbSNP: rs587782664

Total submissions: 11

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	2022-11-28	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464261	SCV000545260	pathogenic	Li-Fraumeni syndrome	2024-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 237 of the TP53 protein (p.Met237Ile). This variant is present in population databases (rs587782664, gnomAD 0.006%). This missense change has been observed in individuals with Li-Fraumeni syndrome (PMID: 11370630; internal data). ClinVar contains an entry for this variant (Variation ID: 142714). Invitae Evidence Modeling incorporating data from in vitro 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: 11370630, 12826609, 17606709, 21343334, 29979965, 30224644). This variant disrupts the p.Met237 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11370630, 12826609, 17606709, 21343334, 29979965, 30224644; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001567943	SCV001791719	pathogenic	not provided	2020-04-15	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31105275, 30840781, 30720243, 30309854, 30216591, 29979965, 28669404, 26787237, 26479578, 27492616, 27895743, 27815358, 23967324, 28029553, 26771088, 26563132, 27347849, 27989700, 28222664, 27074569, 27869737, 28057436, 27657329, 27792260, 21512767, 27059324, 25302557, 7651740, 20080630, 9635828, 12509970, 11166732, 18038118, 7718482, 11238194, 14559903, 20407015, 16492679, 15161705, 9546439, 1915267, 16322298, 10713666, 7588628, 21343334, 17606709, 11370630, 16861262, 12826609)
Baylor Genetics	RCV003462031	SCV004206229	pathogenic	Adrenocortical carcinoma, hereditary	2023-09-23	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001527088	SCV004698107	pathogenic	Li-Fraumeni syndrome 1	2024-02-12	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PS4,PM1,PP1_MOD
Myriad Genetics, Inc.	RCV001527088	SCV004932175	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-16	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 9635828, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000132084	SCV006059707	pathogenic	Hereditary cancer-predisposing syndrome	2024-06-11	criteria provided, single submitter	clinical testing
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, University Hospital Cologne	RCV000785336	SCV000923904	likely pathogenic	Ovarian neoplasm	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