ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.380C>T (p.Ser127Phe) (rs730881999)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000161024 SCV000211743 likely pathogenic not provided 2018-06-29 criteria provided, single submitter clinical testing This variant is denoted TP53 c.380C>T at the cDNA level, p.Ser127Phe (S127F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCC>TTC). TP53 Ser127Phe has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant, but has been reported as a somatic variant in acute lymphoblastic leukemia, melanoma, and other tumors and cell lines (Daniotti 2004, Hof 2011, COSMIC). This variant has demonstrated reduced transcriptional activation for multiple p53 response elements (Dekairelle 2005, Bally 2015) and 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 Ser127Phe 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 TP53 Ser127Phe to be a likely pathogenic variant.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785332 SCV000923900 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Invitae RCV000633384 SCV000754606 uncertain significance Li-Fraumeni syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 127 of the TP53 protein (p.Ser127Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the germline of individuals with a TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 182928). Experimental studies have shown that this missense change results in reduced TP53 transcriptional activation activity (PMID: 12826609). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000606528 SCV000712629 uncertain significance not specified 2016-11-22 criteria provided, single submitter clinical testing The p.Ser127Phe variant in TP53 has not been previously reported in individuals with Li-Fraumeni syndrome or in large population studies. Computational predicti on tools and conservation analysis suggest that the p.Ser127Phe variant may impa ct the protein, though this information is not predictive enough to determine pa thogenicity. In summary, the clinical significance of the p.Ser127Phe variant is uncertain.

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