ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.830G>A (p.Cys277Tyr) (rs763098116)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165199 SCV000215911 likely pathogenic Hereditary cancer-predisposing syndrome 2019-03-13 criteria provided, single submitter clinical testing Deficient protein function in appropriate functional assay(s);Well-characterized mutation at same position;Structural Evidence;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000254809 SCV000322469 likely pathogenic not provided 2016-04-07 criteria provided, single submitter clinical testing This variant is denoted TP53 c.830G>A at the cDNA level, p.Cys277Tyr (C277Y) at the protein level,and results in the change of a Cysteine to a Tyrosine (TGT>TAT). This variant has been observed in one individualwith anaplastic thyroid and prostate cancer (Garg 2015). In vitro-based functional assays have demonstrated thatTP53 Cys277Tyr had reduced or no transactivation activity and exerted a dominant negative effect over wild-type p53(Brachmann 1996, Epstein 1998, Flaman 1998, Dearth 2007, Monti 2011). This variant was not observed inapproximately 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 Cysteine and Tyrosine differ in polarity,charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Cys277Tyr occursat a position that is not conserved and is located in the DNA binding domain (Bode 2004). In silico analyses predictthat this variant is probably damaging to protein structure and function. Based on the currently available evidence, weconsider TP53 Cys277Tyr to be a likely pathogenic variant.
Invitae RCV000456858 SCV000545299 uncertain significance Li-Fraumeni syndrome 2019-12-01 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 277 of the TP53 protein (p.Cys277Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs763098116, ExAC 0.002%). This variant has been reported in an individual with osteosarcoma in the IARC TP53 database (PMID: 27328919, 12759621), an individual with anaplastic thyroid and prostate cancer (PMID: 25365311), and an individual affected with an unspecified cancer (PMID: 17606709). This variant is also known as C238Y and C277Y in the literature. ClinVar contains an entry for this variant (Variation ID: 185722). Experimental studies have shown that this variant has a dominant negative effect over the wild-type TP53 protein, resulting in altered DNA binding and severe reduction of transactivation activity in yeast-based functional assays (PMID: 12826609, 21343334, 8633021, 9482117, 9546439, 9572492, 9627118, 16861262, 11238924). However, other studies have shown that this change retains partial apoptotic and transactivation activity in mammalian cell lines (PMID: 15192123, 16818505). The clinical significance of these results is unknown. 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.
GenomeConnect, ClinGen RCV000254809 SCV001338867 not provided not provided no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 12-26-2018 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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