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

Total submissions: 40

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.
Eurofins NTD, LLC	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	Malignant Colorectal Neoplasm		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
Baylor Genetics	RCV000144669	SCV002030157	pathogenic	Li-Fraumeni syndrome 1	2021-08-24	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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