Submissions for variant NM_000546.6(TP53):c.541C>T (p.Arg181Cys)

gnomAD frequency: 0.00001  dbSNP: rs587782596

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131943	SCV000186999	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-05-30	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. Clinical correlation is advised.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168292	SCV000218970	pathogenic	Li-Fraumeni syndrome	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 181 of the TP53 protein (p.Arg181Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Li-Fraumeni like syndrome or individual(s) who meet Chrompret criteria (PMID: 1581912, 17606709, 23484829, 27501770, 27866339, 28486781). This variant has not been observed in individual(s) with Li-Fraumeni syndrome. It is commonly reported in individuals of Arab ancestry (PMID: 27866339, 28486781). ClinVar contains an entry for this variant (Variation ID: 142624). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 11896595, 12826609, 12917626, 17606709, 20471942, 21343334). This variant disrupts the p.Arg181 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1591732, 11429705, 20128691, 21059199, 21343334, 23175693). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000236276	SCV000293523	uncertain significance	not provided	2021-07-01	criteria provided, single submitter	clinical testing	Published functional studies are inconclusive: conflicting transactivation results, growth suppression ability similar to wild-type, retained or reduced DNA binding abilities, reduced apoptotic activity (Smith 1999, Campomenosi 2001, Monti 2002, Kato 2003, Boutell 2004, Gohler 2005, Schlereth 2010, Malcikova 2010, Monti 2011, Giacomelli 2018, Kotler 2018, Kang 2020); Observed in individuals with breast and other Li-Fraumeni-associated cancers; however, multiple unaffected carriers and at least one homozygous individual have also been reported (Sidransky 1992, Monti 2007, Wang 2013, Kwong 2016, Villani 2016, Lolas Hamameh 2017, Zick 2017, Chan 2018, Sheng 2019, Kwong 2020); Demonstrated incomplete segregation with breast cancer diagnoses in a large Middle Eastern breast cancer kindred (Lolas Hamameh 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 34067731, 33230179, 32722340, 32322110, 34240179, 32303989, 32075053, 33138793, 15510160, 31105275, 27535533, 31119730, 27501770, 31968253, 20471942, 30840781, 30093976, 30720243, 29979965, 28611940, 29086229, 28736647, 28828701, 27866339, 1581912, 14559903, 15221755, 15722483, 11429705, 11896595, 15603511, 26366557, 26887044, 19367569, 28222664, 26771088, 28486781, 27157322, 15077144, 11358831, 17914575, 15580553, 21343334, 20128691, 17606709, 10229196, 23484829, 30224644)
Color Diagnostics, LLC DBA Color Health	RCV000131943	SCV000911991	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-01-09	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). Transgenic mice homozygous for a homolog of this variant showed a slight increase in tumorigenesis (PMID: 31968253). 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, 35033608), 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, 31119730, 33471991). 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.
Baylor Genetics	RCV003474780	SCV004204247	pathogenic	Adrenocortical carcinoma, hereditary	2023-05-03	criteria provided, single submitter	clinical testing
King Laboratory, University of Washington	RCV004544301	SCV005043037	pathogenic	Familial cancer of breast	2024-05-06	criteria provided, single submitter	research	TP53 p.R181C (c.641C>T) was identified in 25 breast cancer patients of Palestinian ancestry. The variant co-segregates with breast cancer in their families, with a lifetime risk to heterozygous females of 81% (s.e. 9%) (PMID: 28486781). Only one of the 25 families fulfilled criteria for Li-Fraumeni syndrome. Across all 25 families, pediatric cancers (diagnosed by age 20y) were not more frequent among first degree relatives of p.R181C-heterozygous breast cancer patients compared to first degree relatives of unrelated age-matched Palestinian breast cancer patients with no pathogenic variant (RR = 0.90, 95% CI [0.23, 3.49]; in-house data). Based on current evidence, p.R181C is interpreted as pathogenic but with risk limited to breast cancer
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000236276	SCV005198839	likely pathogenic	not provided	2023-07-21	criteria provided, single submitter	clinical testing