ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.818G>A (p.Arg273His) (rs28934576)

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Total submissions: 40
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507221 SCV000605425 pathogenic not specified 2017-02-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115738 SCV000186052 pathogenic Hereditary cancer-predisposing syndrome 2017-07-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Well-characterized mutation at same position
Counsyl RCV000013163 SCV000677727 likely pathogenic Li-Fraumeni syndrome 1 2017-02-22 criteria provided, single submitter clinical testing
Database of Curated Mutations (DoCM) RCV000439513 SCV000504661 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422097 SCV000504662 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430161 SCV000504663 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440815 SCV000504664 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422733 SCV000504665 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433409 SCV000504666 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444851 SCV000504667 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424218 SCV000504668 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434044 SCV000504669 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444900 SCV000504670 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424833 SCV000504671 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435547 SCV000504672 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443907 SCV000504673 likely pathogenic Neoplasm of the breast 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424627 SCV000504674 likely pathogenic Adrenocortical carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436207 SCV000504675 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418930 SCV000504676 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428779 SCV000504677 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437210 SCV000504678 likely pathogenic Small cell lung cancer 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419960 SCV000504679 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429822 SCV000504680 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440474 SCV000504681 likely pathogenic Medulloblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424109 SCV000504682 likely pathogenic Chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431361 SCV000504683 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441169 SCV000504684 likely pathogenic Neoplasm 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423826 SCV000504685 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Fulgent Genetics,Fulgent Genetics RCV000515210 SCV000611327 pathogenic Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Carcinoma of colon; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000254693 SCV000149647 pathogenic not provided 2018-07-19 criteria provided, single submitter clinical testing This pathogenic variant is denoted TP53 c.818G>A at the cDNA level and p.Arg273His (R273H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). TP53 Arg273His has been reported in several individuals meeting classic Li-Fraumeni or Chompret criteria, occurring de novo in at least one individual and segregating with disease in affected families (Malkin 1992, Flaman 1995, Varley 1997, Chompret 2000, Cavalier 2005, Wong 2006, Bemis 2007, Ruijs 2010, Sugawara 2011, Wasserman 2015, Schlegelberger 2015, Park 2016). This variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). Additionally, other functional studies have also demonstrated that TP53 Arg273His severely impacts growth suppression, transactivation, and DNA binding, and exerts a dominant-negative effect over wild-type p53 (Dong 2007, Malcikova 2010, Monti 2011, Li 2014, Wasserman 2015). TP53 Arg273His was not observed at a significant allele frequency 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.
GeneKor MSA RCV000115738 SCV000821786 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785345 SCV000923913 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Integrated Genetics/Laboratory Corporation of America RCV000463420 SCV000697450 pathogenic Li-Fraumeni syndrome 2017-02-09 criteria provided, single submitter clinical testing Variant summary: The TP53 c.818G>A (p.Arg273His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/114148 control chromosomes at a frequency of 0.0000263, which does not exceed the estimated maximal expected allele frequency of a pathogenic TP53 variant (0.0000398). The variant has been reported in numerous affected individuals in the literature and the codon location is a known hotspot mutation occurring as a frequent mutation in affected individuals. Functional studies report a dominant negative affect of the variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000463420 SCV000545317 pathogenic Li-Fraumeni syndrome 2019-01-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 273 of the TP53 protein (p.Arg273His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs28934576, ExAC 0.05%). This variant has been observed in numerous individuals and families with Li-Fraumeni syndrome (LFS) or Li-Fraumeni-associated cancers, and has been shown to segregate with disease in affected families (PMID: 9242456, 21484931, 17540308, 1565144, 20693561, 21552135). ClinVar contains an entry for this variant (Variation ID: 12366). This variant is located in the DNA-binding domain of the TP53 protein and is defined as a contact mutation that eliminates an essential DNA contact (PMID: 20516128). A mutant mouse model for this variant develops a variety of tumors and carcinomas by recapitulating LFS (PMID: 15607980). In addition, experimental studies have shown that this variant disrupts transcriptional activity in yeast-based assays (PMID: 12826609) and enhances cell proliferation, invasion, migration, and drug resistance in vitro (PMID: 17636407, 24677579). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000254693 SCV000692068 pathogenic not provided no assertion criteria provided clinical testing
Mendelics RCV000463420 SCV000839110 pathogenic Li-Fraumeni syndrome 2018-07-02 criteria provided, single submitter clinical testing
OMIM RCV000013163 SCV000033410 pathogenic Li-Fraumeni syndrome 1 1993-01-01 no assertion criteria provided literature only
OMIM RCV000013164 SCV000033411 pathogenic Anaplastic thyroid carcinoma 1993-01-01 no assertion criteria provided literature only
Pathway Genomics RCV000013163 SCV000190004 pathogenic Li-Fraumeni syndrome 1 2014-07-24 no assertion criteria provided clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000254693 SCV000602280 pathogenic not provided 2017-04-26 criteria provided, single submitter clinical testing

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