ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.832C>T (p.Pro278Ser) (rs17849781)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522600 SCV000617072 pathogenic not provided 2018-02-15 criteria provided, single submitter clinical testing This pathogenic variant is denoted TP53 c.832C>T at the cDNA level, p.Pro278Ser (P278S) at the protein level, and results in the change of a Proline to a Serine (CCT>TCT). This variant has been reported as a germline pathogenic variant in a child with a glioma from a family meeting Chompret criteria and is a common somatic variant observed in a variety of tumor types (Bougeard 2001, Brachmann 2004, Forbes 2015). Both in vitro and in vivo functional assays have shown TP53 Pro278Ser to greatly reduce or abolish transactivation and apoptotic activity and result in a dominant-negative effect (Epstein 1998, Flaman 1998, Bougeard 2001, Campomenosi 2001, de Vries 2002, Dearth 2007, Monti 2011). Consistent with these results, 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 Pro278Ser was not observed 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.
Ambry Genetics RCV000562528 SCV000664791 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification,Insufficient evidence
Invitae RCV000633344 SCV000754566 uncertain significance Li-Fraumeni syndrome 2017-09-15 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 278 of the TP53 protein (p.Pro278Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in families affected with Li-Fraumeni syndrome (PMID: 11370630, 15993273, 16258005). ClinVar contains an entry for this variant (Variation ID: 376642). Experimental studies have shown that this missense change disrupts TP53 transactivational activity (PMID: 11370630, 12826609, 21343334). 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.
Database of Curated Mutations (DoCM) RCV000432977 SCV000509034 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439725 SCV000509035 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421997 SCV000509036 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432228 SCV000509037 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444293 SCV000509038 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426679 SCV000509039 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433428 SCV000509040 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443572 SCV000509041 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427714 SCV000509042 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437941 SCV000509043 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442821 SCV000509044 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427094 SCV000509045 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435645 SCV000509046 likely pathogenic Neoplasm of the breast 2016-05-31 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785527 SCV000924099 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

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