ClinVar Miner

Submissions for variant NM_001126112.2(TP53):c.328C>T (p.Arg110Cys) (rs587781371)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131196 SCV000186146 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-04 criteria provided, single submitter clinical testing Conflicting evidence
Invitae RCV000195648 SCV000254629 uncertain significance Li-Fraumeni syndrome 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 110 of the TP53 protein (p.Arg110Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs587781371, ExAC 0.02%). This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 142206). This variant has been reported to affect TP53 protein function (PMID: 12826609, 9290701, 31081129). Different missense substitutions at this codon (p.Arg110Pro and p.Arg110Leu) have been determined to be pathogenic (PMID: 12826609, 21552135, 23894400, 23897043, 24076587, 16778209, 24076587, 21445056, Invitae). This suggests that the arginine 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.
GeneDx RCV000414039 SCV000491052 uncertain significance not specified 2016-05-10 criteria provided, single submitter clinical testing The R110C variant in the TP53 gene has been previously reported as a somatic variant in multiple neoplasms, but has not been reported in the germline (for examples, see Konishi et al., 1996; Siroy et al., 2014; Singh et al., 2016). The R110C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R110C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved. In silico analysis predicts this variant is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in the same residue (R110P, R110H, R110L) have been reported in the Human Gene Mutation Database in association with TP53-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. We consider it to be a variant of uncertain significance.
Color RCV000131196 SCV000686732 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing

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