ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.542G>A (p.Arg181His)

gnomAD frequency: 0.00003  dbSNP: rs397514495
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 14
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131382 SCV000186358 likely pathogenic Hereditary cancer-predisposing syndrome 2020-06-29 criteria provided, single submitter clinical testing The p.R181H variant (also known as c.542G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 542. The arginine at codon 181 is replaced by histidine, an amino acid with highly similar properties. This alteration has been identified in a proband with early-onset breast cancer who also met Chompret criteria for TP53 testing (Borresen A et al. Cancer Res. 1992 Jun 1;52(11):3234-6), in an individual diagnosed with breast cancer at age 29 and a family history of multiple cancers (Heymann S et al. Radiat. Oncol. 2010 Nov 8;5:104), and also in an individual with adrenocortical carcinoma and clinical history of neurofibromatosis type 1 (Raymond VM et al. J. Clin. Endocrinol. Metab. 2013 Jan;98(1):E119-25). Functional studies in yeast have shown significant levels of reduced transactivation activity with the p.R181H variant (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul 8;100(14):8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9). Other functional studies have shown that p.R181H causes a defect in promoter binding and transactivation of apoptotic target genes, causing a loss of apoptotic activity (Schlereth K et al. Mol. Cell 2010 May;38(3):356-68; Wang W et al. Genes Dev. 1996 May;10(10):1219-32), but was similar to wild type in that it does not bind proteins specific for the mutant conformation of the p53 protein (Frebourg et al. Proc Natl Acad Sci U.S.A. 1992 Jul;89(14):6413-7), and shows proficient growth suppression in human cells (Kotler E et al. Mol. Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 10;50:1381-1387). This alteration demonstrated a partially reduced ability to bind DNA (Malcikova et al. Biol. Chem. 2010; 391(2-3):197-205). In addition, other missense alterations impacting this codon (p.R181C, p.R181L, and p.R181P) have been reported as associated with TP53​-related disease and causing impaired function (Sidransky D et al. Cancer Res. 1992;15;52(10):2984-6; Villani A et al. Lancet Oncol. 2016 Sep;17(9):1295-305; Krutikova V et al. Eur. J. Cancer. 2005 Jul;41(11):1597-603; Kyritsis AP et al. J. Natl. Cancer Inst. 1994 Mar 2;86(5):344-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on current evidence, p.R181H 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 RCV000168247 SCV000218918 pathogenic Li-Fraumeni syndrome 2021-11-25 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 181 of the TP53 protein (p.Arg181His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 1591732, 21059199, 1631137, Invitae). A review of approximately 50 individuals with this variant revealed they were less likely to meet clinical criteria for Li-Fraumeni syndrome compared to carriers of other well defined TP53 pathogenic variants (Invitae). This suggests this variant may be associated with varying or atypical clinical presentation. It is commonly reported in individuals of Arabic ancestry (PMID: 1581912, 17606709, 23484829, 27501770, 27866339, 28486781). ClinVar contains an entry for this variant (Variation ID: 142320). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 20128691, 21343334, 29979965, 30224644). 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: 1581912, 17606709, 23484829, 27501770, 27866339, 28486781). 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 RCV000255239 SCV000322072 likely pathogenic not provided 2022-10-12 criteria provided, single submitter clinical testing Observed in individuals with early-onset breast and other Li-Fraumeni-related cancers, but does not appear to result in classic Li-Fraumeni syndrome (Borreson et al., 1992; Heymann et al., 2010; Raymond et al., 2013; Leongamornlert et al., 2014; Tung et al., 2015; O'Neill et al., 2017; Shindo et al., 2017; Brand et al., 2018; Mersch et al., 2018; Qian et al., 2018; Baek et al., 2019); Published functional studies demonstrate defective binding and transactivation of apoptotic target genes with a consequent impact on apoptotic activity, mixed transactivation of other p53 response elements, but no impact on growth suppression (Wang et al., 1996; Flaman et al., 1998; Campomenosi et al., 2001; Kato et al., 2003; Monti et al., 2007; Malcikova et al., 2010; Schlereth et al., 2010; Monti et al., 2011; Hekmat-Scafe et al., 2016; Kotler et al., 2018; Giacomelli et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21059199, 11793474, 24729566, 27586204, 17311302, 7981076, 8308926, 31543368, 30840781, 1591732, 20128691, 9546439, 17606709, 21343334, 20471942, 27101868, 26650777, 26484312, 25625332, 15580553, 24449472, 14559903, 1631137, 26762747, 27873457, 11429705, 25186627, 29979965, 28724667, 28767289, 29522266, 23175693, 28861920, 15221755, 18818522, 28772290, 26000489, 30067863, 30653764, 30264118, 24556621, 29300620, 29077256, 31056747, 31115261, 8675009, 1581912, 31026031, 30720243, 31119730, 15925506, 30352134, 30224644, 31105275, 31447099, 32998877, 32676327, 32923878, 33818021, 33880204, 33194542, 33245408, 31948886, 32029870, 33230179, 15510160, 34282142, 12826609, 32817165, 33858029, 34240179)
Counsyl RCV000576528 SCV000677774 likely pathogenic Li-Fraumeni syndrome 1 2017-03-16 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000131382 SCV000686749 likely pathogenic Hereditary cancer-predisposing syndrome 2020-10-27 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine 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 reported conflicting findings on variant protein activities in yeast transactivation assays, human cell growth suppression assays, human cell proliferation assay, and TP53 tumor suppressor-associated activities (PMID: 12826609, 30224644, 29979965, 20471942 and IARC database). The IARC database reports observation of this variant in 12 individuals affected with Li-Fraumeni syndrome or Li-Fraumeni-like syndrome (http://mutantp53.broadinstitute.org/). This variant has been reported in multiple individuals affected with early-onset breast cancer and family history of multiple cancers, who meet Chompret criteria for Li-Fraumeni syndrome (PMID: 1591732, 1631137, 21059199; Color internal data). A family study has shown this variant to segregate with breast cancer and leiomyosarcoma in three siblings (PMID: 1631137). This variant also has been observed in an individual affected with late-onset adrenocortical carcinoma, pheochromocytoma and glioblastoma multiforme, who had been clinically diagnosed with neurofibromatosis type 1 (PMID: 23175693). This variant has been identified in 4/282728 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon, p.Arg181Cys and p.Arg181Pro, are associated with disease (ClinVar variation ID: 125689 and 59756), indicating that arginine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000168247 SCV000731671 likely pathogenic Li-Fraumeni syndrome 2020-02-13 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Mendelics RCV000989718 SCV001140260 likely pathogenic Squamous cell carcinoma of the head and neck 2019-05-28 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000255239 SCV001449803 likely pathogenic not provided 2015-03-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000168247 SCV001774661 likely pathogenic Li-Fraumeni syndrome 2021-07-27 criteria provided, single submitter clinical testing Variant summary: TP53 c.542G>A (p.Arg181His) results in a non-conservative amino acid change located in the p53, DNA-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251324 control chromosomes. c.542G>A has been reported in the literature in individuals affected with features of atypical Li-Fraumeni Syndrome and breast cancer (example, Borresen_1992, Heymann_2010, Frebourg_1992, Alyami_2021). An ascertainment of one family with this variant, identified 3 transmissions of the variant allele and 1 transmissions of the reference allele to affected individuals (Frebourg_1992). These data indicate that the variant may be associated with disease. Multiple publications report conflicting experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in severe deficiency based on the mean transactivation capacity across four different reporter strains (example, Monti_2011). However, another study reported a neutral effect on growth of malignant cells in-vitro with retained structural features of the WT protein and the somatic loss of the mutant allele in a tumor from a family reporting this variant (Frebourg_1992). Multple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genetic Services Laboratory,University of Chicago RCV000255239 SCV002067416 pathogenic not provided 2019-12-05 criteria provided, single submitter clinical testing DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.542G>A, in exon 5 that results in an amino acid change, p.Arg181His. This sequence change has been described in the gnomAD database with a low population frequency of 0.0014% (dbSNP rs397514495). The p.Arg181His change affects a highly conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Arg181His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This pathogenic sequence change has been previously reported in multiple individuals with TP53-related cancers such as breast cancer, adrenocortical carcinoma, and pancreatic cancer (PMIDs: 1591732, 1631137, 21059199, 30653764). Functional studies have demonstrated that the p.Arg181His change may impact protein function (PMIDs: 15580553, 21343334, 20128691). Furthermore, other nucleotide changes affecting the Arg181 residue have also been reported in individuals with TP53-related cancers suggesting that this residue is functionally and clinically important (PMIDs:1581912, 8308926, 15925506).
Genome-Nilou Lab RCV000131382 SCV002582381 likely pathogenic Hereditary cancer-predisposing syndrome 2022-06-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000576528 SCV002583041 likely pathogenic Li-Fraumeni syndrome 1 2022-06-18 criteria provided, single submitter clinical testing
CZECANCA consortium RCV001391195 SCV001593121 likely pathogenic Carcinoma of pancreas 2021-03-04 no assertion criteria provided case-control
University Health Network,Princess Margaret Cancer Centre RCV001527471 SCV001738488 pathogenic Familial cancer of breast 2021-03-19 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.