ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.753C>G (p.Ile251Met) (rs878854074)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000564022 SCV000672414 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000633326 SCV000754548 uncertain significance Li-Fraumeni syndrome 2017-12-14 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 251 of the TP53 protein (p.Ile251Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Li-Fraumeni-associated cancers (PMID: 8550239, 17606709). Experimental studies in yeast and human cell lines have shown that this missense change partially impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609, 20128691, 21343334). A different missense substitution at this codon (p.Ile251Leu) has been reported to segregate with Li-Fraumeni syndrome in two families (PMID: 21305319, 27501770), and has been observed to impair the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). This suggests that the isoleucine residue is critical for TP53 protein function and that other missense substitutions at this position may also be damaging. 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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