ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.737T>A (p.Met246Lys) (rs587780074)

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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 RCV000574219 SCV000664441 likely pathogenic Hereditary cancer-predisposing syndrome 2017-05-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Well-characterized mutation at same position,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification
Invitae RCV000797952 SCV000937542 likely pathogenic Li-Fraumeni syndrome 2018-11-06 criteria provided, single submitter clinical testing This sequence change replaces methionine with lysine at codon 246 of the TP53 protein (p.Met246Lys). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Li-Fraumeni syndrome-associated tumors (Invitae). ClinVar contains an entry for this variant (Variation ID: 480764). Experimental studies in zebrafish and yeast have shown that this missense change impairs the transcriptional transactivation activity and apoptosis of the TP53 protein (PMID: 12826609, 15630097). Moreover, zebrafish homozyous mutants developed malignant peripheral nerve sheath tumors starting at 8.5 months with an incidence of 28% by 16.5 months (PMID: 15630097). This variant disrupts the p.Met246 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 26534844, 8075648), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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