ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.743G>A (p.Arg248Gln) (rs11540652)

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Total submissions: 44
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235221 SCV000149645 pathogenic not provided 2018-10-05 criteria provided, single submitter clinical testing This pathogenic variant is denoted TP53 c.743G>A at the cDNA level, p.Arg248Gln (R248Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has been observed in several Li-Fraumeni or Li-Fraumeni-like families and has also been reported as an apparently de novo heterozygous or mosaic finding in individuals meeting Chompret criteria (Toguchida 1992, Monti 2007, Prochazkova 2009, Masciari 2011, Villani 2011, Behjati 2014, Patrier-Sallebert 2015, Parsons 2016, Sherborne 2016). Functional studies have found that TP53 Arg248Gln impacts DNA binding, apoptosis, growth suppression, and transactivation activities and leads to a dominant-negative effect (Lomax 1998, Dearth 2007, Malcikova 2010, Monti 2011). This variant is also reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional studies by Kato et al. (2003). TP53 Arg248Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on the current evidence, we consider this variant to be pathogenic.
Ambry Genetics RCV000115736 SCV000185472 pathogenic Hereditary cancer-predisposing syndrome 2017-07-17 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,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Other strong data supporting pathogenic classification
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000235221 SCV000232078 pathogenic not provided 2014-06-09 criteria provided, single submitter clinical testing
Invitae RCV000197114 SCV000253851 pathogenic Li-Fraumeni syndrome 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 248 of the TP53 protein (p.Arg248Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs11540652, ExAC 0.02%). This variant was reported in multiple individuals and families affected with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 1565143, 17606709, 21601526, 7887414, 21305319). ClinVar contains an entry for this variant (Variation ID: 12356). Experimental studies have shown that this missense change severely affects the functional activity of the p53 protein, abolishing its DNA-binding and transcriptional transactivation activities. This variant is classified as a severe deficiency allele with possible dominant-negative inhibitory effects (PMID: 21343334, 17606709, 20128691). For these reasons, this variant has been classified as Pathogenic.
University of Washington Department of Laboratory Medicine,University of Washington RCV000115736 SCV000266133 likely pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
Color RCV000115736 SCV000686766 pathogenic Hereditary cancer-predisposing syndrome 2015-04-14 criteria provided, single submitter clinical testing
Counsyl RCV000013150 SCV000785422 likely pathogenic Li-Fraumeni syndrome 1 2017-07-27 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115736 SCV000821785 pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000197114 SCV000839112 pathogenic Li-Fraumeni syndrome 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763417 SCV000894154 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 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000013150 SCV000033397 pathogenic Li-Fraumeni syndrome 1 2000-05-15 no assertion criteria provided literature only
Pathway Genomics RCV000013150 SCV000190000 pathogenic Li-Fraumeni syndrome 1 2014-07-24 no assertion criteria provided clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148913 SCV000190659 pathogenic Sarcoma 2014-06-01 no assertion criteria provided research
Database of Curated Mutations (DoCM) RCV000445244 SCV000504693 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426606 SCV000504694 likely pathogenic Neoplasm 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437291 SCV000504695 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419135 SCV000504696 likely pathogenic Neoplasm of the breast 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426359 SCV000504697 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437935 SCV000504698 likely pathogenic Myelodysplastic syndrome 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420727 SCV000504699 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430513 SCV000504700 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441226 SCV000504701 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417916 SCV000504702 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428591 SCV000504703 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438410 SCV000504704 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421194 SCV000504705 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432778 SCV000504706 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439963 SCV000504707 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421893 SCV000504708 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432587 SCV000504709 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000445235 SCV000504710 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426233 SCV000504711 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433424 SCV000504712 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444656 SCV000504713 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427709 SCV000504714 likely pathogenic Medulloblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437518 SCV000504715 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420303 SCV000504716 likely pathogenic Small cell lung cancer 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424869 SCV000504717 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435533 SCV000504718 likely pathogenic Chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Donald Williams Parsons Laboratory,Baylor College of Medicine RCV000013150 SCV000599966 pathogenic Li-Fraumeni syndrome 1 2012-12-27 no assertion criteria provided research This variant has been previously reported as disease-causing and was found once in our study maternally inherited in a 2-year-old female with neuroblastoma, in a family meeting criteria for Li-Fraumeni (history of early breast, brain tumors, rhabdomyosarcoma).
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000235221 SCV000692073 pathogenic not provided no assertion criteria provided clinical testing
Genome Sciences Centre,British Columbia Cancer Agency RCV000589336 SCV000693734 pathogenic Malignant Colorectal Neoplasm 2016-04-12 no assertion criteria provided research
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785344 SCV000923912 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center RCV000790860 SCV000930032 likely pathogenic Lymphoma 2019-07-25 no assertion criteria provided clinical testing

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