Total submissions: 22
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
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. |
Invitae | RCV000464261 | SCV000545260 | likely pathogenic | Li-Fraumeni syndrome | 2023-12-04 | 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; Invitae). ClinVar contains an entry for this variant (Variation ID: 142714). 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: 11370630, 12826609, 17606709, 21343334, 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. |
Gene |
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, |
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, |
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]. |
Database of Curated Mutations |
RCV000435205 | SCV000508880 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000417987 | SCV000508881 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
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 |
RCV000441079 | SCV000508883 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000420354 | SCV000508884 | likely pathogenic | Ovarian serous cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431054 | SCV000508885 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000441725 | SCV000508886 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000422710 | SCV000508887 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000433401 | SCV000508888 | likely pathogenic | Gastric adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440576 | SCV000508889 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423376 | SCV000508890 | likely pathogenic | Brainstem glioma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432346 | SCV000508891 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Mayo Clinic Laboratories, |
RCV000581940 | SCV000692075 | uncertain significance | not specified | no assertion criteria provided | clinical testing | ||
German Consortium for Hereditary Breast and Ovarian Cancer, |
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 |