ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.747G>T (p.Arg249Ser) (rs28934571)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000579519 SCV000686767 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-09 criteria provided, single submitter clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785491 SCV000924063 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Invitae RCV000464372 SCV000545320 uncertain significance Li-Fraumeni syndrome 2016-08-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 249 of the TP53 protein (p.Arg249Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TP53-related disease. However, this variant has been identified as a hot spot in hepatocellular carcinoma and is the 7th most frequent single codon TP53 mutation found in human cancer biopsies (PMID: 1849234, 19756158, 20538734, 15095302, 17311302). ClinVar contains an entry for this variant (Variation ID: 12352). Experimental studies have shown that this missense change affects TP53 protein structure and disrupts protein function (PMID: 15703170, 15982667, 9405613, 12826609, 20538734, 15060172, 18477611). In summary, this variant is a rare missense change that disrupts protein function. While it is absent from the population and reported in many cancer cell biopsies, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
OMIM RCV000013145 SCV000033392 pathogenic Hepatocellular carcinoma 1992-05-02 no assertion criteria provided literature only
OMIM RCV000013146 SCV000033393 pathogenic Carcinoma of cervix 1992-05-02 no assertion criteria provided literature only
University of Washington Department of Laboratory Medicine,University of Washington RCV000464372 SCV000886463 pathogenic Li-Fraumeni syndrome 2018-05-25 criteria provided, single submitter research The TP53 variant designated as NM_000546.5:c.747G>T (p.Arg249Ser) is classified as pathogenic. This variant has not been reported in public population databases. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and shows a likelihood ratio of 7.52 to 1 that this allele explains cancer in the family (Thompson et al, 2003, PMID:2900794). Computer software programs (SIFT, Polyphen-2, PROVEAN) predict that this variant is likely to have a damaging effect. Experimental functional studies provide evidence that this variant can lead to loss of function by disrupting protein structure (Gouas et al, 2010, PMID: 20538734; Lee et al, 2008, PMID: 18477611; Butler et al, 2005, PMID: 15982667; Joerger et al, 2005, PMID: 15703170; Chan et al, 2004, PMID:15060172; Kato et al, 2003, PMID: 12826609; Bullock et al, 1997, PMID: 9405613). Additionally, analysis of breast tumor in one member of the observed family shows loss of heterozygosity for the allele with this TP53 variant in breast tissue, which adds moderate evidence that this variant is pathogenic. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about 99% probability of pathogenicity, which is consistent with a classification of pathogenic. The combined results are consistent with a classification of pathogenic in the context of Li-Fraumeni syndrome. This variant is expected to alter TP53 function and increase risks related to Li-Fraumeni syndrome associated cancers. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

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