ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.714T>G (p.Cys238Trp) (rs193920789)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000203823 SCV000260275 pathogenic Li-Fraumeni syndrome 2015-08-28 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tryptophan at codon 238 of the TP53 protein (p.Cys238Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. This variant is not been reported in any individual in population databases (rs193920789, no frequency) and has not been reported in any affected individual in the literature. ClinVar contains an entry for this variant (Variation ID: 161515). Experimental studies have shown that this missense change is a severe deficiency allele, resulting in significantly decreased transactivation activity of TP53, and that it may act in a dominant negative fashion, reducing the transactivation activity of the wild-type allele (PMID: 12826609, 21343334). The cysteine residue at codon 238 is known to bind Zn2+ and to stabilize the structure of the TP53 DNA binding domain (PMID: 8023157). Furthermore, other amino acid substitutions at this codon have been reported in affected patients, namely Cys238Tyr and Cys238Ser. These sequence changes have also been described as severe deficiency alleles (PMID: 12826609, 21343334). This indicates that the cysteine 238 may be critical for proper protein function. For these reasons, this variant has been classified as Pathogenic.
Science for Life laboratory, Karolinska Institutet RCV000149049 SCV000088691 unknown Malignant tumor of prostate no assertion criteria provided not provided Converted during submission to Uncertain significance.

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