ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.329G>C (p.Arg110Pro) (rs11540654)

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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 RCV000222678 SCV000278043 likely pathogenic Hereditary cancer-predisposing syndrome 2015-08-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Other data supporting pathogenic classification
Invitae RCV000231991 SCV000285189 pathogenic Li-Fraumeni syndrome 2018-10-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 110 of the TP53 protein (p.Arg110Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in three families who meet the criteria for classical Li-Fraumeni syndrome (LFS), or who are highly suggestive of having LFS, and has been reported to occur de novo in one affected individual (PMID: 21552135, 23894400, 29070607, Invitae). ClinVar contains an entry for this variant (Variation ID: 233627). Experimental studies have shown that this missense change disrupts p53 transactivation in vitro and in vivo, and results in decreased cellular apoptosis after stress (PMID: 12826609, 23897043, 24076587). A different missense substitution at this codon (p.Arg110Leu) has been observed to be de novo in an individual affected with LFS-associated cancers (Invitae) and has been determined to be pathogenic (PMID: 16778209, 24076587, 21445056). 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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