ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.742C>T (p.Arg248Trp) (rs121912651)

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Total submissions: 35
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115735 SCV000212766 pathogenic Hereditary cancer-predisposing syndrome 2018-04-03 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,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles RCV000735293 SCV000854446 pathogenic Pectus excavatum; Acute myeloid leukemia; Short stature; Cognitive impairment; Webbed neck; Pancytopenia; Abnormality of the tongue criteria provided, single submitter clinical testing
Counsyl RCV000013140 SCV000488942 pathogenic Li-Fraumeni syndrome 1 2016-07-25 criteria provided, single submitter clinical testing
Database of Curated Mutations (DoCM) RCV000419032 SCV000504848 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429777 SCV000504849 likely pathogenic Neoplasm of the breast 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440422 SCV000504850 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423184 SCV000504851 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433905 SCV000504852 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441091 SCV000504853 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423804 SCV000504854 likely pathogenic Chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434504 SCV000504855 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442243 SCV000504856 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424415 SCV000504857 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431689 SCV000504858 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444845 SCV000504859 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425083 SCV000504860 likely pathogenic Myelodysplastic syndrome 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435803 SCV000504861 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418495 SCV000504862 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425682 SCV000504863 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436398 SCV000504864 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419150 SCV000504865 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429884 SCV000504866 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440560 SCV000504867 likely pathogenic Medulloblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419857 SCV000504868 likely pathogenic Small cell lung cancer 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430543 SCV000504869 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441557 SCV000504870 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424308 SCV000504871 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431508 SCV000504872 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438698 SCV000504873 likely pathogenic Neoplasm 2015-07-14 no assertion criteria provided literature only
GeneDx RCV000213057 SCV000149644 pathogenic not provided 2018-07-02 criteria provided, single submitter clinical testing This variant is denoted TP53 c.742C>T at the cDNA level, p.Arg248Trp (R248W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has been observed in several individuals and families meeting Li-Fraumeni or Li-Fraumeni like criteria (Malkin 1990, Hwang 2003, Birch 1994, Monti 2007, Rossbach 2008, Serra 2013, Villani 2016). Functional assays have consistently found that TP53 Arg248Trp significantly impacts transcriptional activation of typical p53 targets and causes a dominant-negative effect (Willis 2004, Grochova 2008, Monti 2011). Additionally, 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). TP53 Arg248Trp is considered a hot spot" mutant and is one of the most common somatic variants in human cancer (Brachmann 2004, Willis 2004, Xu 2014). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). TP53 Arg248Trp 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 RCV000785485 SCV000924057 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Invitae RCV000168242 SCV000218912 pathogenic Li-Fraumeni syndrome 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 248 of the TP53 protein (p.Arg248Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs121912651, ExAC 0.001%). This variant has been reported in the literature as one of the most commonly identified variants in individuals with Li-Fraumeni syndrome. It is also associated with a high incidence of breast cancer (PMID: 24573247, 23172776, 23950206, 1978757). ClinVar contains an entry for this variant (Variation ID: 12347) Experimental studies have shown that this missense change severely disrupts essential activities of the TP53 protein (PMID: 17606709, 20128691, 21343334, 23172776). Another missense substitution at this codon (p.Arg248Gln) has also been determined to be deleterious (PMID: 17606709, 20128691), confirming that the Arg248 residue is important for TP53 protein function. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000168242 SCV000204074 pathogenic Li-Fraumeni syndrome 2017-07-10 criteria provided, single submitter clinical testing The p.Arg248Trp variant in TP53 is a well-established pathogenic variant for Li- Fraumeni syndrome (IARC TP53 Database, http://p53.iarc.fr; ClinVar Variation ID 12347). It has also been identified in 1/111704 European chromosomes by the Geno me Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs12191 2651); however this frequency is low enough to be consistent with the frequency of Li-Fraumeni syndrome in the general population. Amino acid position 248 is a known TP53 mutation hotspot, with several different variants (including p.Arg248 Gln) that have been well reported in individuals with TP53-associated cancers (F reed-Pastor 2012, Xu 2014). Furthermore, both in vitro and in vivo functional st udies support that this variant impacts protein function (Frebourg 1992, Dittmer 1993). In summary, the p.Arg248Trp variant meets criteria to be classified as p athogenic for Li-Fraumeni syndrome in an autosomal dominant manner.
Mendelics RCV000168242 SCV000839113 pathogenic Li-Fraumeni syndrome 2018-07-02 criteria provided, single submitter clinical testing
OMIM RCV000013140 SCV000033387 pathogenic Li-Fraumeni syndrome 1 1992-07-15 no assertion criteria provided literature only

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