ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.737T>C (p.Met246Thr) (rs587780074)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492075 SCV000581125 likely pathogenic Hereditary cancer-predisposing syndrome 2014-09-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Well-characterized mutation at same position,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function in appropriate functional assay(s)
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785245 SCV000923813 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Invitae RCV000704600 SCV000833554 uncertain significance Li-Fraumeni syndrome 2018-03-06 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 246 of the TP53 protein (p.Met246Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with osteosarcoma (PMID: 25896519). ClinVar contains an entry for this variant (Variation ID: 428886). Experimental studies in yeast have shown that this variant impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609, 20407015). A different missense substitution at this codon (p.Met246Val) has been determined to be pathogenic (PMID: 26534844, 19558493, 8075648, 17606709). This suggests that the methionine residue is critical for TP53 protein function and that other missense substitutions at this position may also be pathogenic. 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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