Total submissions: 35
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000226657 | SCV001142565 | pathogenic | Li-Fraumeni syndrome | 2019-08-28 | reviewed by expert panel | curation | This variant is within a codon that is an established hotspot in the TP53 gene (PM1; PMID: 2046748). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3). 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 at least 3 probands meeting classic Li-Fraumeni syndrome criteria and at least 2 probands meeting Chompret criteria (PS4; PMID: 11370630, 24122735, 20522432, 12885464). In summary, TP53 c.733G>A; p.Gly245Ser 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, PP3, PS3, PS4. |
Ambry Genetics | RCV000130147 | SCV000184981 | pathogenic | Hereditary cancer-predisposing syndrome | 2018-02-06 | criteria provided, single submitter | clinical testing | The p.G245S pathogenic mutation (also known as c.733G>A), located in coding exon 6 of the TP53 gene, results from a G to A substitution at nucleotide position 733. The glycine at codon 245 is replaced by serine, an amino acid with similar properties. This mutation has been reported in multiple individuals with clinical histories suggestive of Li-Fraumeni syndrome (Toguchida J et al. N. Engl. J. Med. 1992 May;326:1301-8; Wong P et al. Gastroenterology. 2006 Jan;130:73-9; Melhem-Bertrandt A et al. Cancer. 2012 Feb;118:908-13; Giacomazzi J et al. Cancer. 2013 Dec;119:4341-9; Jia Y et al. Cancer Biol. Ther. 2014 Aug;15:970-4; Churpek JE et al. Cancer. 2016 Jan 15;122(2):304-11). Functional studies performed by Monti et al. led authors to characterize this alteration as a severe deficiency allele (1% mean residual activity compared to wild type p53) with a dominant negative effect (Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-9). Additional functional studies confirm a decrease in p53 functionality as compared to wild type (Zerdoumi Y et al. Hum Mol Genet. 2017 Jul 15;26(14):2812). This alteration has been reported as a somatic mutation 456 times in various tumors, and as a germline mutation 40 times by the IARC TP53 database (Petitjean A et al. IARC TP53 database [November 2015]. Hum. Mutat. 2007 Jun;28:622-9). In addition, this mutation was confirmed to be de novo in one child with a choroid plexus carcinoma in our internal cohort (Ambry data). Based on the available evidence, this alteration is classified as a pathogenic mutation. |
EGL Genetic Diagnostics, |
RCV000154014 | SCV000203642 | pathogenic | not provided | 2013-12-12 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000154014 | SCV000211745 | pathogenic | not provided | 2018-10-12 | criteria provided, single submitter | clinical testing | This variant is denoted TP53 c.733G> A at the cDNA level, p.Gly245Ser (G245S) at the protein level, and results in the change of a Glycine to a Serine (GGC>AGC). This variant was observed in multiple individuals with personal and/or family histories suggestive of Li-Fraumeni syndrome, occurring de novo in at least one individual (Toguchida 1992, Wong 2006, Melham-Bertrand 2012, Giacomazzi 2013, Brozou 2017, Nordfors 2018, Diets 2018). Functional studies have shown that TP53 Gly245Ser impacts DNA binding, transcriptional activation, and growth suppression activities, and leads to a dominant-negative effect (Malcikova 2010, Monti 2011, Kotler 2018). This variant is also reported as having non-functional transactivation activity in the International Agency for Research on Cancer TP53 database based on functional studies by Kato et al. (2003). TP53 Gly245Ser was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic. |
Invitae | RCV000226657 | SCV000285210 | pathogenic | Li-Fraumeni syndrome | 2020-01-08 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with serine at codon 245 of the TP53 protein (p.Gly245Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs28934575, ExAC 0.001%). This variant has been reported to segregate in multiple families with Li-Fraumeni syndrome (LFS) or LFS-like syndrome (PMID: 1565143, 24122735, 17311302), and has been observed in many individuals with LFS-related cancers (PMID: 20522432, 11370630, 15925506, 21761402, 16401470, 27621308, 26225655). ClinVar contains an entry for this variant (Variation ID: 12365). This variant is located within the DNA binding domain, which is important for proper TP53 protein function (PMID: 26205489). Experimental studies have shown that this missense change disrupts the ability of TP53 to bind to DNA and significantly decreases its transcriptional transactivation activity (PMID: 12826609, 20128691, 21343334, 12917626, 15722483). For these reasons, this variant has been classified as Pathogenic. |
Counsyl | RCV000144669 | SCV000677743 | pathogenic | Li-Fraumeni syndrome 1 | 2016-11-29 | criteria provided, single submitter | clinical testing | |
Color | RCV000130147 | SCV000691616 | pathogenic | Hereditary cancer-predisposing syndrome | 2016-05-19 | criteria provided, single submitter | clinical testing | |
Laboratory for Molecular Medicine, |
RCV000226657 | SCV000711788 | pathogenic | Li-Fraumeni syndrome | 2016-06-16 | criteria provided, single submitter | clinical testing | The p.Gly245Ser variant in TP53 has been reported in >15 individuals with TP53-a ssociated cancers. It also segregated with disease in at least 8 affected relati ves from multiple families (Varley 1997; Trkova 2003). This variant has also bee n identified in 1/66734 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs29834575). In vitro functional s tudies demonstrate that the p.Gly245Ser variant has a dominant negative effect ( Marutani 1999). In summary, this variant meets criteria to be classified as path ogenic for Li-Fraumeni syndrome in an autosomal dominant manner based upon segre gation studies, low frequency in controls, and functional evidence. |
Mendelics | RCV000226657 | SCV000839114 | pathogenic | Li-Fraumeni syndrome | 2018-07-02 | criteria provided, single submitter | clinical testing | |
Clinical Genetics Karolinska University Hospital, |
RCV000154014 | SCV001450404 | likely pathogenic | not provided | 2018-12-03 | criteria provided, single submitter | clinical testing | |
Institute of Biochemistry, |
RCV001270274 | SCV001450491 | pathogenic | Colorectal cancer | criteria provided, single submitter | case-control | ||
OMIM | RCV000013162 | SCV000033409 | pathogenic | Li-Fraumeni-like syndrome | 1995-01-01 | no assertion criteria provided | literature only | |
Pathway Genomics | RCV000144669 | SCV000190001 | pathogenic | Li-Fraumeni syndrome 1 | 2014-07-24 | no assertion criteria provided | clinical testing | |
CSER _CC_NCGL, |
RCV000148909 | SCV000190655 | likely pathogenic | Adenocarcinoma | 2014-06-01 | no assertion criteria provided | research | |
Database of Curated Mutations |
RCV000421457 | SCV000504874 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432120 | SCV000504875 | likely pathogenic | Adenocarcinoma of stomach | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000442506 | SCV000504876 | likely pathogenic | Ovarian Serous Cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425581 | SCV000504877 | likely pathogenic | Neoplasm | 2015-07-14 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432898 | SCV000504878 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000442529 | SCV000504879 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426307 | SCV000504880 | likely pathogenic | Uterine Carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436979 | SCV000504881 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419767 | SCV000504882 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426990 | SCV000504883 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437643 | SCV000504884 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000420452 | SCV000504885 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000430925 | SCV000504886 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438107 | SCV000504887 | likely pathogenic | Brainstem glioma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000417419 | SCV000504888 | likely pathogenic | Adenocarcinoma of prostate | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000428113 | SCV000504889 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438801 | SCV000504890 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Mayo Clinic Genetic Testing Laboratories, |
RCV000154014 | SCV000692074 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Tampere Brain Tumor Research Consortium, |
RCV000587017 | SCV000693711 | pathogenic | Atypical teratoid/rhabdoid tumor | no assertion criteria provided | research | ||
Tampere Brain Tumor Research Consortium, |
RCV000588736 | SCV000693712 | pathogenic | Astrocytoma, anaplastic | no assertion criteria provided | research | ||
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne, |
RCV000785316 | SCV000923884 | likely pathogenic | Neoplasm of ovary | 2018-12-01 | no assertion criteria provided | research |