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

gnomAD frequency: 0.00001  dbSNP: rs28934575

Total submissions: 36

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	2024-08-05	reviewed by expert panel	curation	The NM_000546.6: c.733G>A variant in TP53 is a missense variant predicted to cause substitution of glycine by serine at amino acid 245 (p.Gly245Ser). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with a strongly LFS-associated cancer totaling 2 phenotype points (PS2_Moderate; Internal lab contributor: SCV000184981.8). This variant has been reported in an additional individual meeting Classical criteria and 11 individuals meeting Revised Chompret criteria. Based on this evidence, this variant scores 8 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs: 11370630, 32156018, 32888145, 33245408, 34670578, 35974385, 20522432, 24122735, Internal lab contributor: SCV000184981.8). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors: SCV000184981.8). This variant has an allele frequency of 0.000002543 (3/1179926 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PMID: 8023157 ) (PM1). Computational predictor scores (BayesDel = 0.5536; Align GVGD = Class C55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2_Moderate, PS4_Very Strong, PP4_Moderate, PM2_Supporting, PS3, PM1, PP3. (Bayesian Points: 20; VCEP specifications version 2.0; 7/24/2024)
Ambry Genetics	RCV000130147	SCV000184981	pathogenic	Hereditary cancer-predisposing syndrome	2024-03-07	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 variant has been reported in multiple individuals with clinical and family histories consistent with Li-Fraumeni syndrome (Toguchida J et al. N. Engl. J. Med. 1992 May;326:1301-8; Bougeard G et al. J Med Genet, 2001 Apr;38:253-7; Trkova M et al. Cancer Genet Cytogenet, 2003 Aug;145:60-4; Wong P et al. Gastroenterology. 2006 Jan;130:73-9; Ruijs MW et al. J Med Genet, 2010 Jun;47:421-8; Giacomazzi J et al. Cancer. 2013 Dec;119:4341-9). This variant has been determined to be the result of a de novo mutation or germline mosaicism in in one child with a choroid plexus carcinoma (Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast-based assays (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 and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Eurofins Ntd Llc (ga)	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226657	SCV000285210	pathogenic	Li-Fraumeni syndrome	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 245 of the TP53 protein (p.Gly245Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with Li-Fraumeni syndrome (LFS) or LFS-like syndrome and LFS-related cancers (PMID: 1565143, 11370630, 15925506, 16401470, 17311302, 20522432, 21761402, 24122735, 26225655, 27621308). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12365). 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: 12826609, 12917626, 15722483, 20128691, 21343334, 26205489). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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 Diagnostics, LLC DBA Color Health	RCV000130147	SCV000691616	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-18	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 multiple individuals affected with either classic Li-Fraumeni syndrome (PMID: 11370630, 12885464 32156018, 32817165, 33163847, 33840814, 34709361, 35974385) or meeting the Chompret criteria for Li-Fraumeni syndrome, including individuals with early-onset breast cancer (PMID:20522432, 32888145, 32888145, 33245408, 34529667, 359743855; Color Health internal data). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000154014	SCV000692074	pathogenic	not provided	2022-03-15	criteria provided, single submitter	clinical testing	PP3, PP5, PM1, PM2_moderate, PS3, PS4
Laboratory for Molecular Medicine, Mass General Brigham 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 and Genomics, 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
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].
Sema4, Sema4	RCV000130147	SCV002532707	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-01	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002496337	SCV002810979	pathogenic	Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Bone osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma; Colorectal cancer; Bone marrow failure syndrome 5	2022-05-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000226657	SCV003844261	pathogenic	Li-Fraumeni syndrome	2023-02-27	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.733G>A (p.Gly245Ser) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251472 control chromosomes. c.733G>A has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome, osteosarcoma and other cancers (examples: Toguchida_1992, Giacomazzi_2013, Melhem-Bertrandt_2012, Bougeard_2001). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in impaired DNA binding, transcriptional activation, and growth suppression activities, with a dominant-negative effect observed (Monti_2011, Kato_2003, etc). 13 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories, including an expert panel, classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000144669	SCV003928102	pathogenic	Li-Fraumeni syndrome 1	2023-04-06	criteria provided, single submitter	clinical testing	The TP53 c.733G>A (p.Gly245Ser) missense change has a maximum subpopulation frequency of 0.0040% in gnomAD v2.1.1 (http://gnomad.broadinstitute.org). This variant has been reported in individuals with LFS-associated cancers (PMID: 11370630, 24122735, 20522432, 12885464). Computational evidence supports a deleterious effect of this variant on protein function and transactivation assays show a low functioning allele according to Kato et al., and evidence of loss of function and a dominant negative effect according to Giacomelli et al. (PMID 12826609, 30224644). This variant is a somatic hotspot variant in tumors. In summary, this variant meets criteria to be classified as pathogenic.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000144669	SCV003936121	pathogenic	Li-Fraumeni syndrome 1	2023-07-04	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 245 of the TP53 protein (p.Gly245Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with Li-Fraumeni syndrome (LFS) or LFS-like syndrome and LFS-related cancers (PMID: 1565143, 11370630, 15925506, 16401470, 17311302, 20522432, 21761402, 24122735, 26225655, 27621308). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12365). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) expected to disrupt TP53 protein function. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 12917626, 15722483, 20128691, 21343334, 26205489). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003460464	SCV004206210	pathogenic	Adrenocortical carcinoma, hereditary	2024-03-27	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000154014	SCV005198835	pathogenic	not provided	2023-04-11	criteria provided, single submitter	clinical testing
Molecular Diagnostics Laboratory, Catalan Institute of Oncology	RCV000130147	SCV005407747	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-05	criteria provided, single submitter	clinical testing	c.733G>A, located in exon 7 of the TP53 gene, is predicted to result in the substitution of Glycine by Serine at codon 245, p.(Gly245Ser). It is located in a mutational hotspot (PM1). This variant is found in 1/268258 alleles at a frequency of 0.0003% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C55; BayesDel: 0.55) (PP3). Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID: 30224644) (PS3). At least, this variant has been reported in 7 individuals affected with a TP53-related phenotype, which awards 4.5 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (PMID: 11370630, 32156018, 32888145, 34670578, 20522432, 24122735) (PS4). It has been reported in ClinVar as a pathogenic variant, LOVD, CancerHotspots. Based on the currently available information, c.733G>A is classified as a pathogenic variant according to ClinGen-TP53 Guidelines version 1.4.
Institute of Human Genetics, University Hospital Muenster	RCV004797759	SCV005419299	pathogenic	See cases	2020-11-03	criteria provided, single submitter	clinical testing	ACMG categories: PS3,PS4,PM1,PM2_sup,PP3,PP4
All of Us Research Program, National Institutes of Health	RCV000226657	SCV005425722	pathogenic	Li-Fraumeni syndrome	2024-04-25	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 multiple individuals meeting the Chompret criteria for Li-Fraumeni syndrome, including individuals with early-onset breast cancer (PMID: 20522432, 32888145; Color Health internal data), two individuals with colorectal cancer (PMID: 32000721), 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.
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
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, University Hospital Cologne	RCV000785316	SCV000923884	likely pathogenic	Ovarian neoplasm	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	Ovarian neoplasm	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
Laboratory for Genotyping Development, RIKEN	RCV003162245	SCV002758167	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
Laboratory of Urology, Hospital Clinic de Barcelona	RCV003332080	SCV004040610	pathogenic	Malignant tumor of urinary bladder		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003914832	SCV004730974	pathogenic	TP53-related disorder	2023-12-06	no assertion criteria provided	clinical testing	The TP53 c.733G>A variant is predicted to result in the amino acid substitution p.Gly245Ser. This variant has been identified in individuals with a personal or family history of Li-Fraumeni syndrome and related cancers (Toguchida. 1992. PubMed ID: 1565143; Wong. 2006. PubMed ID: 16401470; Melhem-Bertrandt. 2012. PubMed ID: 21761402; Giacomazzi. 2013. PubMed ID: 24122735; Table S4, Bhai. 2021. PubMed ID: 34326862; Table S2, Guindalini. 2022. PubMed ID: 35264596). Functional analysis showed that this variant resulted in severe deficiency of transactivation activity and TP53 functionality (Table S1, Monti. 2011. PubMed ID: 21343334; Table 1, Zerdoumi. 2017. PubMed ID: 28472496). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD and has been reported in ClinVar by multiple sources as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/12365/). This variant is interpreted as pathogenic.