ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.524G>A (p.Arg175His) (rs28934578)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131301 SCV000186273 pathogenic Hereditary cancer-predisposing syndrome 2017-08-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Structural Evidence,Deficient protein function in appropriate functional assay(s)
GeneDx RCV000213054 SCV000211798 pathogenic not provided 2018-11-14 criteria provided, single submitter clinical testing This variant is denoted TP53 c.524G>A at the cDNA level and p.Arg175His (R175H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). TP53 Arg175His has been reported in several individuals meeting clinical diagnostic criteria for Li-Fraumeni syndrome or Chompret criteria for TP53 testing (Birch 1994, Kyritsis 1994, McIntyre 1994, Chompret 2000, Bougeard 2001, Malkin 2001, Potzsch 2002, Walsh 2006, Wong 2006, Choong 2012, Melhem-Bertrandt 2012, Zerdoumi 2013, Maxwell 2016, Park 2016, Zerdoumi 2017) and is considered a common hotspot" variant present in diverse cell lines and tumors (Soussi 2014, COSMIC, IARC TP53 Database). Functional studies have consistently found this variant to impact control of cell growth as well as DNA binding and transcriptional activation (Dittmer 1993, Malcikova 2010, Monti 2011, Wasserman 2015), and TP53 Arg175His is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Arg175His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant 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, we consider TP53 Arg175His to be pathogenic."
Invitae RCV000204931 SCV000261917 pathogenic Li-Fraumeni syndrome 2018-11-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 175 of the TP53 protein (p.Arg175His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs28934578, ExAC 0.001%). This variant has been reported in individuals and families affected with Li-Fraumeni syndrome, osteosarcoma, breast cancer and ovarian carcinoma (PMID: 8825920, 8164043, 21761402, 22006311, 16401470). ClinVar contains an entry for this variant (Variation ID: 12374). This is a well-studied variant, located in a known mutation hotspot within the central DNA-binding domain of TP53 (PMID: 23263379, 20516128, 24573247, 12007217). It causes not only loss of the tumor suppressor function of the TP53 protein, but also oncogenic gain-of-function (PMID: 23792586, 23263379). In addition, a mouse model of Li-Fraumeni syndrome was engineered using this missense variant (PMID: 15607980, 15607981), and these mice developed a variety of carcinomas and reproduced the metastatic phenotype. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000013173 SCV000488375 pathogenic Li-Fraumeni syndrome 1 2016-03-18 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000204931 SCV000731790 pathogenic Li-Fraumeni syndrome 2017-07-24 criteria provided, single submitter clinical testing The p.Arg175His variant in TP53 has been reported in >16 individuals with Li-Fra umeni syndrome, and segregated with disease in 3 affected relatives from 1 famil y (McIntyre 1994, Varley 1997, Wong 2006, Bougeard 2008, Walsh 2011, Melhem-Bert randt 2012, Park 2016). This variant has also been reported by another clinical laboratory in ClinVar (Variation ID# 12374). In vitro functional studies provide some evidence that the p.Arg175His variant may impact protein function (Kogan-S akin 2011, Grugan 2013) and an in-vivo mouse model has shown that this variant c auses TP53-related tumors (Liu 2010). Additionally, the p.Arg175His variant has been identified in 1/111550 European chromosomes by gnomAD (http://gnomad.broadi nstitute.org). Computational prediction tools and conservation analysis suggest that the p.Arg175His variant may impact the protein and 3 other amino acid chang es at this position (Leu, Gly, Cys) have been associated with Li-Fraumeni syndro me (HGMD database; Stenson 2017). In summary, this variant meets criteria to be classified as pathogenic for Li-Fraumeni syndrome in an autosomal dominant manne r based on segregation studies, increased prevalence in affected individuals, ve ry low frequency in controls and functional evidence. ACMG/AMP Criteria applied: PS4, PP1, PS3, PM2.
PreventionGenetics,PreventionGenetics RCV000213054 SCV000806241 pathogenic not provided 2017-04-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763419 SCV000894156 pathogenic Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Carcinoma of colon; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000131301 SCV000905051 pathogenic Hereditary cancer-predisposing syndrome 2015-04-15 criteria provided, single submitter clinical testing
OMIM RCV000013173 SCV000033420 pathogenic Li-Fraumeni syndrome 1 2005-08-01 no assertion criteria provided literature only
Pathway Genomics RCV000013173 SCV000189994 pathogenic Li-Fraumeni syndrome 1 2014-07-24 no assertion criteria provided clinical testing
Institute of Biochemistry, Molecular Biology and Biotechnology,University of Colombo RCV000239398 SCV000297733 pathogenic Malignant tumor of esophagus 2016-07-29 no assertion criteria provided clinical testing SIFT:Deleterious (score: 0) MutationTaster:Disease causing (p-value: 1)
Database of Curated Mutations (DoCM) RCV000421746 SCV000504891 likely pathogenic Neoplasm 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428918 SCV000504892 not provided Neoplasm of the breast 2016-03-10 no assertion provided literature only
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000213054 SCV000692083 pathogenic not provided no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785352 SCV000923920 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

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