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 2020-03-28 criteria provided, single submitter clinical testing The p.R181C variant (also known as c.541C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 541. The arginine at codon 181 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in one individual diagnosed with breast cancer at age 33 and melanotic spindle cell carcinoma of the mediastinum at age 35 and in another individual with rhabdomyosarcoma, adrenal cortical carcinoma, and osteosarcoma (Sidransky D et al. Cancer Res. 1992;15;52(10):2984-6; Villani A et al. Lancet Oncol. 2016 Sep;17(9):1295-305). In addition, one study found this alteration in six family members ranging in age from 16 to 60; however, only two of them were affected with cancer (Wang PY et al. N. Engl. J. Med. 2013;368(11):1027-32). This alteration has more recently been reported in several families that have multiple early-onset cancers but do not meet Li-Fraumeni syndrome criteria, although some met Chrompret criteria, leading the authors to suggest this is a pathogenic mutation with an attenuated phenotype (Zick A et al. Fam. Cancer. 2017 Apr;16:295-301; Lolas Hamameh S et al. Int. J. Cancer. 2017 Aug;141:750-756). Yeast based functional studies have shown this alteration to have significantly reduced transactivation capacity compared to wild type, as well as dominant negative properties with several response elements (Monti P et al. Mol Cancer Res. 2011;9(3):271-9; IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003;8;100(14):8424-9). However, this alteration showed DNA binding activity similar to wild type (Malcikova J et al. Biol. Chem.;391:197-205), and was proficient at growth suppression in human cells (Kotler E et al. Mol. Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). A different alteration which occurs at the same codon, p.R181H (c.542G>A) has been seen in individuals with breast cancer and Li-Fraumeni syndrome (Heymann S et al. Radiat Oncol. 2010;5:10; Børresen AL et al. Cancer Res. 1992;52(11):3234-6). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on current evidence, p.R181C is interpreted as a likely pathogenic moderate risk allele that may not be associated with classic LFS but rather leads to increased risk of developing a TP53-related cancer. Clinical correlation is advised.
Invitae RCV000168292 SCV000218970 pathogenic Li-Fraumeni syndrome 2020-10-19 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 observed 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.
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.
Color Health, Inc RCV000131943 SCV000911991 likely pathogenic Hereditary cancer-predisposing syndrome 2020-06-17 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 181 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies are inconsistent about the variant impact on TP53 protein function. While some studies have shown that the mutant protein shows partial reduction of transactivation activity (IARC database and PMID: 12826609) and normal function in human cell growth suppression assays (PMID: 29979965, 30224644), other studies have shown that this variant partially or fully impairs transcriptional transactivation activity, DNA binding activity, and apoptotic activity of the TP53 protein (PMID: 10229196, 12917626, 17606709, 20128691, 20471942, 21343334). This variant has been reported in multiple individuals suspected of having Li-Fraumeni syndrome or affected with Li-Fraumeni syndrome-associated tumors (PMID: 17606709, 27501770, 27866339), including an adult affected with glioblastoma multiform at 70 years old (PMID: 27866339) and a child affected with rhabdomyosarcoma, adrenocortical carcinoma and osteosarcoma, who died at age 3 years old (PMID: 27501770). This variant has been reported in over 15 individuals affected with breast cancer, most of whom showed early-onset with family history of breast cancer or other Li-Fraumeni syndrome-associated tumors (PMID: 1581912, 27866339, 28486781). Among the reported breast cancer-affected females, four of them showed age of onset prior to age 31 years old (PMID: 27866339, 28486781). This variant has been shown to segregate with breast cancer in six individuals from two families of Arab ancestry, where incomplete penetrance was observed (PMID: 28486781). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant p.Arg181His occurring at the same codon is known to be pathogenic, based on the observation in multiple individuals affected with Li-Fraumeni syndrome-associated tumors, who showed strong family history (Clinvar variation ID: 142320). This indicates that arginine at the codon 181 position is important for TP53 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. This variant may be hypomorphic and may display reduced penetrance relative to typical pathogenic TP53 variants.

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