ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.799C>T (p.Arg267Trp) (rs55832599)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130398 SCV000185257 likely pathogenic Hereditary cancer-predisposing syndrome 2017-12-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Well-characterized mutation at same position,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Structural Evidence,Deficient protein function in appropriate functional assay(s)
GeneDx RCV000413074 SCV000491277 likely pathogenic not provided 2016-06-22 criteria provided, single submitter clinical testing The R267W variant has been published previously as a germline variant in a patient with breast cancer (Melhem-Bertrandt et al., 2012). However, no familial segregation studies have been published to our knowledge. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R267W is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the DNA binding domain that is not conserved; however, in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown R267W abolishes the transactivation activity of the TP53 protein (Pekova et al., 2011). Therefore, we consider this variant to be likely pathogenic.
Invitae RCV000538977 SCV000629873 likely pathogenic Li-Fraumeni syndrome 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 267 of the TP53 protein (p.Arg267Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Li-Fraumeni syndrome (PMID: 28573494, 29324801), and in an individual affected with multiple tumors including breast fibroadenoma, subependymoma, melanoma and sessile serrated adenoma (PMID: 27501770), as well as in an unaffected individual with a family history of Li-Fraumeni syndrome (PMID: 23484829), and an individual affected with breast cancer (PMID: 21761402). ClinVar contains an entry for this variant (Variation ID: 141764). Experimental studies have shown that this missense change disrupts TP53 transcriptional transactivation and results in decreased cellular apoptosis after stress (PMID: 16861262, 24076587, 12826609). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color RCV000130398 SCV000686775 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-08 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763416 SCV000894153 likely 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

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