ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.145G>C (p.Asp49His) (rs587780728)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123095 SCV000166395 uncertain significance Li-Fraumeni syndrome 2018-09-18 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 49 of the TP53 protein (p.Asp49His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs587780728, ExAC 0.01%). This variant has been reported in an individual affected with Li-Fraumeni-like syndrome, and several other individuals with family histories of cancer, but none fulfilling the criteria for Li-Fraumeni or Li-Fraumeni-like syndromes (PMID: 27545002). ClinVar contains an entry for this variant (Variation ID: 135948). Experimental studies have shown that this missense change disrupts the transcriptional transactivation function of the TP53 protein (PMID: 12826609) and increases VEGF expression (PMID: 12901974). In addition, two studies have shown that in combination with p.Asp48His, this variant affects TP53 binding to RPA (PMID: 9207066, 15489903) and homologous recombination suppression (PMID: 15489903), but the effect of this variant alone on these aspects of TP53 function has not been tested, therefore the clinical significance of these results are 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.
Ambry Genetics RCV000129275 SCV000184035 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000410497 SCV000488754 uncertain significance Li-Fraumeni syndrome 1 2016-06-07 criteria provided, single submitter clinical testing
Color RCV000129275 SCV000686722 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing

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