ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.733G>A (p.Gly245Ser) (rs28934575)

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Total submissions: 39
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen 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, Eurofins Clinical Diagnostics RCV000154014 SCV000203642 pathogenic not provided 2013-12-12 criteria provided, single submitter clinical testing
GeneDx RCV000154014 SCV000211745 pathogenic not provided 2021-06-28 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: impaired DNA binding, transcriptional activation, and growth suppression activities, with a dominant-negative effect observed (Kato 2003, Malcikova 2010, Monti 2011, Kotler 2018); Not observed at 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: 23334668, 16401470, 27045317, 28222664, 30592087, 31081129, 20128691, 17606709, 21665182, 19367569, 1565143, 24573247, 25637381, 21343334, 25503501, 24122735, 26822949, 21761402, 17311302, 12676907, 26786923, 26641009, 24835218, 26225655, 27621308, 28369373, 28573494, 29602769, 28724667, 29025599, 29338689, 29979965, 28472496, 28975465, 23538418, 30076369, 29093764, 30720243, 30322717, 30093976, 30840781, 29263802, 30816478, 15951970, 31105275, 32000721, 27535533, 15510160, 29351919, 28929227, 32475984, 32156018, 33300245)
Invitae RCV000226657 SCV000285210 pathogenic Li-Fraumeni syndrome 2020-10-18 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 Health, Inc RCV000130147 SCV000691616 pathogenic Hereditary cancer-predisposing syndrome 2020-11-23 criteria provided, single submitter clinical testing This missense variant replaces glycine with serine at codon 245 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 non-functional in transactivation assays (PMID: 11370630, 12826609, 15781620) and in cell growth assays (PMID: 29979965, 30224644). This variant has been reported in two individuals affected with classic Li-Fraumeni syndrome (PMID: 11370630, 12885464). This variant has also been observed in four individuals meeting the Chompret criteria for Li-Fraumeni syndrome, including three individuals with early-onset breast cancer (PMID: 20522432, 32888145) and a child with medulloblastoma whose mother was affected with early-onset breast cancer (PMID: 24122735). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized 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,Karolinska University Hospital RCV000154014 SCV001450404 likely pathogenic not provided 2018-12-03 criteria provided, single submitter clinical testing
Institute of Biochemistry, Molecular Biology and Biotechnology,University of Colombo RCV001270274 SCV001450491 pathogenic Colorectal cancer criteria provided, single submitter case-control
Department of Pediatric Oncology, Hematology and Clinical Immunology,University Clinics Duesseldorf RCV000130147 SCV001482283 pathogenic Hereditary cancer-predisposing syndrome criteria provided, single submitter research
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, University of Washington RCV000148909 SCV000190655 likely pathogenic Adenocarcinoma 2014-06-01 no assertion criteria provided research
Database of Curated Mutations (DoCM) RCV000421457 SCV000504874 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432120 SCV000504875 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442506 SCV000504876 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425581 SCV000504877 likely pathogenic Neoplasm 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432898 SCV000504878 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442529 SCV000504879 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426307 SCV000504880 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436979 SCV000504881 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) 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 (DoCM) RCV000426990 SCV000504883 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437643 SCV000504884 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420452 SCV000504885 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430925 SCV000504886 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438107 SCV000504887 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417419 SCV000504888 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428113 SCV000504889 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438801 SCV000504890 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Mayo Clinic Laboratories, Mayo Clinic RCV000154014 SCV000692074 pathogenic not provided no assertion criteria provided clinical testing
Tampere Brain Tumor Research Consortium,University of Tampere RCV000587017 SCV000693711 pathogenic Atypical teratoid/rhabdoid tumor no assertion criteria provided research
Tampere Brain Tumor Research Consortium,University of Tampere RCV000588736 SCV000693712 pathogenic Astrocytoma, anaplastic no assertion criteria provided research
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785316 SCV000923884 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354825 SCV001549535 pathogenic Familial ovarian cancer no assertion criteria provided clinical testing The TP53 p.Gly245Ser variant was identified in 8 of 2224 proband chromosomes (frequency: 0.004) from Spanish, Dutch, British, and American individuals or families with Li-Fraumeni syndrome, and Li-Fraumeni syndrome with breast cancer (BRCA1/2 negative and early onset, or with a family history of multiple primary cancers, or HER-2 positive) or early onset CRC, and was not identified in 300 chromosomes from healthy individuals (Llovet 2017 , Martin 2003, Maxwell 2014, Ruijis 2009, Eccles 2016, Wong 2006). The variant falls within 1 of 5 conserved domains for which the majority of disease associated mutations (hotspots) occur (codons 175, 245, 248, 249 and 273); the variant is a structural mutant that is moderately destabilized when compared to wild-type p53 and has partial DNA binding thereby affecting the protein’s transcriptional activity, as evidenced through multiple studies using molecular dynamics simulations, crystallography/NMR Spectroscopy (Martin 2003, Lepre 2017, Wong 1999, Merabet 2010, Joerger 2006).The variant was also identified in dbSNP (ID: rs28934575) “With Likely pathogenic,Pathogenic allele”, ClinVar (classified pathogenic by Ambry Genetics, EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), GeneDx, Invitae, Pathway Genetics and OMIM; and likely pathogenic by CSER_CC_NCGL (University of Washington Medical Center)), Clinvitae (1x), Cosmic (in numerous tumour tissue types: brain, breast, liver, lung, pancreatic, bladder, oesophageal, colon, stomach,ovarian, prostate, and uterine), UMD TP53 Mutation Database, and Database of germline p53 mutations. The variant was not identified in Genesight-COGR, LOVD 3.0, and IARC TP53 Database. The variant was identified in control databases in 1 of 277132 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017), seen in the African population in 1 of 23998 chromosomes (freq: 0.00004), while not observed in the Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Gly245 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Ser variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
University Health Network,Princess Margaret Cancer Centre RCV000785316 SCV001738482 pathogenic Neoplasm of ovary 2021-03-19 no assertion criteria provided clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital,University of Health Sciences RCV001642222 SCV001852738 pathogenic Breast carcinoma 2021-09-10 no assertion criteria provided clinical testing

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