ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.736A>T (p.Met246Leu) (rs483352695)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000470073 SCV000545318 uncertain significance Li-Fraumeni syndrome 2018-04-26 criteria provided, single submitter clinical testing This sequence change replaces methionine with leucine at codon 246 of the TP53 protein (p.Met246Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with chronic lymphocytic leukemia (CLL) (PMID: 26837699). In addition, a different nucleotide change resulting in the same amino acid substitution (c.746A>C, M246L) was identified in a patient with acute myeloid leukemia (AML) (PMID: 26781615). ClinVar contains an entry for this variant (Variation ID: 406586). Experimental studies have shown that this missense change adversely affects protein function (PMID: 19558493, 12826609). 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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