ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.1009C>T (p.Arg337Cys) (rs587782529)

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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 RCV000131726 SCV000186766 pathogenic Hereditary cancer-predisposing syndrome 2017-09-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Well-characterized mutation at same position,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other strong data supporting pathogenic classification,Rarity in general population databases (dbsnp, esp, 1000 genomes)
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785479 SCV000924051 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Invitae RCV000475086 SCV000545330 pathogenic Li-Fraumeni syndrome 2018-04-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 337 of the TP53 protein (p.Arg337Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs587782529, ExAC 0.01%). This sequence change has been reported in many individuals and families with Li-Fraumeni like syndrome with some evidence of segregation with disease (PMID: 17606709, 9150393, 20478780, 9452042, 18511570). ClinVar contains an entry for this variant (Variation ID: 142536). Experimental studies using model organisms and mammalian cells have shown that this sequence change partially disrupts TP53 protein function (PMID: 12826609, 9150393, 20128691, 21343334, 9704931, 9704930). A different missense substitution at this codon (p.Arg337His) has been determined to be pathogenic (PMID: 20407015, 12826609, 9704930, 16033918, 10864200). This suggests that the arginine residue is critical for TP53 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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