ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.542G>A (p.Arg181His) (rs397514495)

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Total submissions: 10
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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 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 181 of the TP53 protein (p.Arg181His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs397514495, ExAC 0.003%). 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 other well defined TP53 pathogenic variants (Invitae). This suggests this variant may be associated with varying or atypical clinical presentation. ClinVar contains an entry for this variant (Variation ID: 142320). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 protein function (PMID: 12826609, 30224644, 29979965, 20128691, 21343334). This variant disrupts the p.Arg181 amino acid residue in TP53. Another variant, p.Arg181Cys, that disrupts this residue has been determined to be pathogenic and has been described as a suspected founder mutation among Arabic populations (PMID: 28486781, 1581912, 27866339, 17606709, 23484829, 27501770). 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 2018-08-24 criteria provided, single submitter clinical testing This variant is denoted TP53 c.542G>A at the cDNA level, p.Arg181His (R181H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). TP53 Arg181His has been reported in several individuals with early-onset breast cancer, another with prostate cancer, and a woman with adrenocortical carcinoma, pheochromocytoma, and glioblastoma multiforme all diagnosed after age 50 who was reported to also carry a diagnosis of Neurofibromatosis type 1 (B?rresen 1992, Heymann 2010, Raymond 2013, Tung 2015). Functional assays evaluating transactivation, DNA binding, and growth suppression have demonstrated mixed results (Malcikova 2010, Monti 2011, Hekmat-Scafe 2016, Kotler 2018) consistent with this variant being 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). However, TP53 Arg181His has been shown to be defective in promoter binding and transactivation specifically of apoptotic target genes, with a consequent impact on apoptotic activity observed (Flaman 1998, Campomenosi 2001, Monti 2007, Schlereth 2010, Monti 2011). TP53 Arg181His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on the currently available evidence, we consider this to be a likely pathogenic variant; however, based on published case reports, it may not result in classic Li-Fraumeni syndrome.
Counsyl RCV000576528 SCV000677774 likely pathogenic Li-Fraumeni syndrome 1 2017-03-16 criteria provided, single submitter clinical testing
Color Health, Inc 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,Partners HealthCare 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
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

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