ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs28934575
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Total submissions: 51
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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 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)
Invitae RCV000226657 SCV000285210 pathogenic Li-Fraumeni syndrome 2024-01-05 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 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: 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 (Invitae). 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 2022-04-27 criteria provided, single submitter clinical testing PP3, PP5, PM1, PM2, 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
PreventionGenetics, part of Exact Sciences RCV003914832 SCV004730974 pathogenic TP53-related disorder 2023-12-06 criteria provided, single submitter 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004526594 SCV005040279 pathogenic Multiple acyl-CoA dehydrogenase deficiency 2023-02-27 criteria provided, single submitter clinical testing Variant summary: ETFA c.733G>A (p.Val245Ile) results in a conservative amino acid change located in the Electron transfer flavoprotein, alpha subunit, C-terminal domain (IPR014731) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. Two predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251078 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.733G>A has been reported in the literature in individuals affected with Glutaric Aciduria, Type 2a. These report(s) do not provide unequivocal conclusions about association of the variant with Glutaric Aciduria, Type 2a. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004540999 SCV005040823 pathogenic Xeroderma pigmentosum 2023-02-27 criteria provided, single submitter clinical testing Variant summary: ERCC2 c.733G>A (p.Asp245Asn) results in a conservative amino acid change located in the DEAD2 domain (IPR010614) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 250228 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.733G>A in individuals affected with Xeroderma Pigmentosum and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
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 Gastric adenocarcinoma 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 Prostate adenocarcinoma 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
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 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
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

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