ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.376T>G (p.Tyr126Asp) (rs886039483)

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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 RCV000568595 SCV000672378 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000255685 SCV000322113 likely pathogenic not provided 2015-06-08 criteria provided, single submitter clinical testing This variant is denoted TP53 c.376T>G at the cDNA level, p.Tyr126Asp (Y126D) at the protein level, and results in the change of a Tyrosine to an Aspartic Acid (TAC>GAC) in exon 5. This variant was observed in at least one individual with breast and peritoneal cancer (Walsh 2011). This variant has also been observed as a somatic variation in breast, lung, esophageal, pancreatic, and follicular lymphoma tumors (Duddy 2000, Kan 2010, Biankin 2012, Dulak 2013, Green 2013). Functional studies have shown that this variant results in impaired transactivation of BAX and PIG3, as well as of p21 at a biologically relevant temperature (Campomenosi 2001). Additionally, Duddy et al. (2000) showed in a yeast based assay (FASAY) that TP53 Tyr126Asp lacks transactivation activity. TP53 Tyr126Asp 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. Since Tyrosine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Tyr126Asp occurs at a position that is conserved across species and is located in the DNA-binding domain and the region of interaction with HIPK1, ZNF385A, FBXO42 and AXIN1 (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, we consider TP53 Tyr126Asp to be a variant, expected pathogenic.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785482 SCV000924054 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Invitae RCV000705124 SCV000834106 uncertain significance Li-Fraumeni syndrome 2018-04-04 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with aspartic acid at codon 126 of the TP53 protein (p.Tyr126Asp). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a single family affected with breast and peritoneal cancer (PMID: 22006311), but it was referred as c.376T>A, p.Tyr126Asp in the literature. ClinVar contains an entry for this variant (Variation ID: 265333). Experimental studies have shown that this missense change impairs the transcriptional transactivation activity of p53 (PMID: 12826609, 11229518, 11429705). 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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