ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.541C>T (p.Arg181Cys) (rs587782596)

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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 RCV000131943 SCV000186999 likely pathogenic Hereditary cancer-predisposing syndrome 2017-12-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Other data supporting pathogenic classification,Deficient protein function in appropriate functional assay(s),Well-characterized mutation at same position
Color RCV000131943 SCV000911991 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-01 criteria provided, single submitter clinical testing
GeneDx RCV000236276 SCV000293523 uncertain significance not provided 2017-12-18 criteria provided, single submitter clinical testing This variant is denoted TP53 c.541C>T at the cDNA level, p.Arg181Cys (R181C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). TP53 Arg181Cys has been observed in individuals with breast and other Li-Fraumeni-associated cancers; however, multiple unaffected carriers have also been reported (Sidransky 1992, Monti 2007, Wang 2013, Kwong 2016, Villani 2016, Lolas Hamameh 2017, Zick 2017). Although Lolas Hamameh et al. (2017) found this variant to segregate with disease in one breast cancer kindred, other Li-Fraumeni-related cancers were not present in this family. In addition, this variant was found to be homozygous in an individual with breast cancer and no reported family history of cancer (Zick 2017). Functional assays have demonstrated mixed results, with TP53 Arg181Cys retaining residual transcriptional activity for a subset of target genes and growth suppression activity similar to wild-type (Smith 1999, Monti 2007, Monti 2011). While one in vitro assay found this variant to reduce apoptosis activity to 30-40% of wild-type, the clinical significance of this level of reduction is unclear (Smith 1999). Consistent with these results, TP53 Arg181Cys is reported as having partially functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). This variant was not observed in large population cohorts (Lek 2016). Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Arg181Cys is located in the DNA binding domain (Bode 2004). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether TP53 Arg181Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000168292 SCV000218970 pathogenic Li-Fraumeni syndrome 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 181 of the TP53 protein (p.Arg181Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Li-Fraumeni syndrome (LFS) or LFS-associated cancers (PMID: 1581912, 17606709, 23484829, 27501770). It has also been shown to segregate with breast cancer and brain tumors in three families (PMID: 28486781, 27866339). In addition, it has been reported as a recurrent, lower-penetrance variant in affected individuals of Arab ancestry (PMID: 27866339, 28486781). ClinVar contains an entry for this variant (Variation ID: 142624). Experimental studies have shown that this missense change affects the transcriptional transactivation activity, DNA-protein complex stability, and apoptotic activity of the TP53 protein (PMID: 11896595, 17606709, 12826609, 12917626, 21343334, 20471942). A different missense substitution at this codon (p.Arg181His) has been determined to be pathogenic (PMID: 1591732, 21059199, 23175693, 20128691, 21343334, 11429705). 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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