ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.770T>A (p.Leu257Gln) (rs28934577)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785553 SCV000924125 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Invitae RCV000469142 SCV000545266 uncertain significance Li-Fraumeni syndrome 2016-09-03 criteria provided, single submitter clinical testing This sequence change replaces leucine with glutamine at codon 257 of the TP53 protein (p.Leu257Gln). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two affected individuals from a single family with Li-Fraumeni syndrome (PMID: 17606709). In a second family, this variant was observed in an individual with TP53-related tumors and two unaffected siblings (PMID: 8134127). ClinVar contains an entry for this variant (Variation ID: 12372). Experimental studies in yeast have shown that this missense change disrupts DNA binding to TP53 responsive elements and transcriptional activation of targets (PMID: 12826609, 20128691, 17606709) and shows a dominant-negative effect on wild-type protein function (PMID: 21343334). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change that has been shown to disrupt protein function in vitro. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
OMIM RCV000013171 SCV000033418 pathogenic Li-Fraumeni-like syndrome 1995-01-01 no assertion criteria provided literature only

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