ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.733G>A (p.Gly245Ser) (rs28934575)

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Total submissions: 32
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130147 SCV000184981 pathogenic Hereditary cancer-predisposing syndrome 2018-02-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family,Well-characterized mutation at same position,Deficient protein function in appropriate functional assay(s)
CSER_CC_NCGL; University of Washington Medical Center RCV000148909 SCV000190655 likely pathogenic Adenocarcinoma 2014-06-01 no assertion criteria provided research
Color RCV000130147 SCV000691616 pathogenic Hereditary cancer-predisposing syndrome 2016-05-19 criteria provided, single submitter clinical testing
Counsyl RCV000144669 SCV000677743 pathogenic Li-Fraumeni syndrome 1 2016-11-29 criteria provided, single submitter clinical testing
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 Neoplasm of the breast 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
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 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.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785316 SCV000923884 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Invitae RCV000226657 SCV000285210 pathogenic Li-Fraumeni syndrome 2019-01-05 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.
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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000154014 SCV000692074 pathogenic not provided no assertion criteria provided clinical testing
Mendelics RCV000226657 SCV000839114 pathogenic Li-Fraumeni syndrome 2018-07-02 criteria provided, single submitter clinical testing
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
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

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