ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.845G>A (p.Arg282Gln) (rs730882008)

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Total submissions: 26
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000235474 SCV000605422 likely pathogenic not specified 2016-11-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000492420 SCV000581106 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
Color RCV000492420 SCV000903415 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-09 criteria provided, single submitter clinical testing
Database of Curated Mutations (DoCM) RCV000428909 SCV000509612 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439593 SCV000509613 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422340 SCV000509614 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429554 SCV000509615 likely pathogenic Neoplasm of the breast 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438489 SCV000509616 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421276 SCV000509617 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431918 SCV000509618 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442318 SCV000509619 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423658 SCV000509620 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434324 SCV000509621 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442471 SCV000509622 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427734 SCV000509623 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433180 SCV000509624 likely pathogenic Non-Hodgkin lymphoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444806 SCV000509625 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426667 SCV000509626 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437335 SCV000509627 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418376 SCV000509628 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425549 SCV000509629 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436164 SCV000509630 likely pathogenic Renal cell carcinoma, papillary, 1 2016-05-31 no assertion criteria provided literature only
GeneDx RCV000767028 SCV000293522 uncertain significance not provided 2018-02-22 criteria provided, single submitter clinical testing This variant is denoted TP53 c.845G>A at the cDNA level, p.Arg282Gln (R282Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant was observed in a patient with neuroblastoma and was reportedly inherited from one of her parents, but the family history was not suggestive of Li-Fraumeni syndrome (Chompret 2000). Functional analyses have found that TP53 Arg282Gln results in varied transactivation or repression abilities across p53 responsive elements (Andreotti 2011, Resnick 2003, Monti 2011, Campomenosi 2001), and this variant is reported as having partially functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Arg282Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. TP53 Arg282Gln occurs at a position that is not conserved and is located in the DNA binding domain (Bode 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether TP53 Arg282Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000709768 SCV000840078 likely pathogenic Li-Fraumeni syndrome 1 2017-09-25 criteria provided, single submitter clinical testing The c.845G>A (p.Arg282Gln) variant in the TP53 gene has been reported as a germline change in two related individuals with a family history of cancer (PMID: 17606709). This variant has also been reported in individuals affected with breast cancer, lung cancer and neuroblastoma (PMID: 26976419, 26787237, 10864200). Experimental studies have shown that this missense change affects TP53 protein structure and function (PMID: 15982667, 19913028). A different pathogenic missense substitution at this codon (p.Arg282Trp) has been reported in multiple cancer patients (PMID: 1565143, 21059199, 21305319, 21761402, 22672556, 11370630, 25584008) suggesting that the arginine residue is critical for TP53 protein. Based upon the above evidence, this c.845G>A, p.Arg282Gln variant is classified as likely pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000226273 SCV000697451 likely pathogenic Li-Fraumeni syndrome 2016-11-18 criteria provided, single submitter clinical testing Variant summary: The TP53 c.845G>A (p.Arg282Gln) variant involves the alteration of a conserved nucleotide in the DNA-binding domain of the protein. 4/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 120540 control chromosomes. This variant has been reported as germline variant in cancer patients. In particular, this variant was observed in a patient with neuroblastoma and was reportedly inherited from one of her parents, but the family history (female patient, diagnosed at age 1 with neuroblastoma, and a maternal aunt with lymphoma diagnosed at 44) was not suggestive of Li-Fraumeni syndrome (Chompret 2000). In addition, one clinical diagnostic laboratory classified this variant as pathogenic while the other clinical lab classified it as VUS, all without evidence to independently evaluate. Functional studies showed that variant decreased but did not abolish the transactivation capacity of TP53. Other two variants involving codon 282 (R282G and R282W) have been reported in affected individuals and are both listed as "pathogenic" by HGMD and ClinVar, and this location is cited in literature as TP53 mutation hotspot (Resnick_PNAS_2003). Taken together, this variant is classified as probably pathogenic until more information regarding co-segregation becomes available.
Invitae RCV000226273 SCV000285213 uncertain significance Li-Fraumeni syndrome 2018-05-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 282 of the TP53 protein (p.Arg282Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two related individuals with a family history of cancer (PMID: 17606709), and individuals affected with breast cancer, lung cancer and neuroblastoma (PMID: 26976419, 26787237, 10864200). ClinVar contains an entry for this variant (Variation ID: 237956). A different missense substitution at this codon (p.Arg282Trp) has been determined to be pathogenic (Invitae), suggesting that the arginine residue might be critical for TP53 protein function. Experimental studies have shown this variant (p.Arg282Gln) only partially impairs the transcriptional transactivation activity of TP53 in yeast-based assays (PMID: 12826609, 21343334, 11429705, 12909720, 12917626, 11896595), and may affect the structural stability of the TP53 protein (PMID: 15982667, 19913028). The clinical significance of these findings is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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