ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.524G>A (p.Arg175His) (rs28934578)

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Total submissions: 22
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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 2018-09-13 criteria provided, single submitter clinical testing The p.R175H pathogenic mutation (also known as c.524G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 524. This changes the amino acid from an arginine to a histidine at codon 175. This alteration occurs at a well-characterized mutation "hotspot" in the functionally critical DNA binding domain, and is associated with a classic LFS-associated tumor spectrum, including osteosarcomas, rhabdomyosarcomas, early onset colon cancer, breast cancer, and pediatric adrenal cortical tumors (McIntyre JF et al. J. Clin. Oncol. 1994 May;12(5):925-930; Varley JM et al. J. Med. Genet. 1995 Dec;32:942-945; Wong P et al. Gastroenterology. 2006 Jan;130:73-79; Hwang SM et al. Korean J. Lab Med. 2008 Dec;28(6):493-497; Melhem-Bertrandt A et al. Cancer. 2012 Feb;118(4):908-13; Choong SS et al. Clin. Genet. 2012 Dec;82(6):564-8; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-17; Park KJ et al. Ann. Lab. Med. 2016 Sep;36:463-8; Dudley B et al. Cancer. 2018 Apr;124(8):1691-1700). Functional studies have shown that this alteration leads to an increase in cell colony growth and classified it as a severe transactivation deficiency allele with less than 25% residual protein activity compared to wildtype alleles (Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-279; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul 8;100(14):8424-9; Wasserman JD et al. J. Clin. Oncol. 2015 Feb;33(6):602-9; Zerdoumi Y et al. Hum. Mol. Genet. 2017 07;26(14):2812). Based on the available evidence, this alteration is classified as a pathogenic mutation.
GeneDx RCV000213054 SCV000211798 pathogenic not provided 2021-01-04 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Kato et al., 2003; Monti et al., 2011; Wasserman et al., 2015; Kotler et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31447099, 31105275, 15510160, 12826609, 19556618, 21343334, 25584008, 29979965, 8118819, 8164043, 10864200, 12200603, 16401470, 22233476, 28369373, 30577483, 30840781, 30093976, 29324801, 30092803, 30720243, 30709875, 28472496, 29753700, 29360550, 28975465, 29470806, 19127115, 29360161, 28818432, 29416795, 27153395, 12610779, 11494139, 11370630, 8308926, 7887414, 8099841, 23792586, 20689556, 15492269, 21426305, 22006311, 24573247, 22286061, 21305319, 17606709, 21761402, 24651015, 20128691, 24729566, 15170137, 29489754, 28861920, 28724667, 15607981, 15607980, 27516001, 27374712, 27714481, 27501770, 27323394, 23172776, 22265402, 21601526, 22851211, 21059199, 20501846, 18511570, 17308077, 16551709, 15951970)
Invitae RCV000204931 SCV000261917 pathogenic Li-Fraumeni syndrome 2020-10-21 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 observed 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 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 Health, Inc RCV000131301 SCV000905051 pathogenic Hereditary cancer-predisposing syndrome 2015-04-15 criteria provided, single submitter clinical testing
Institute of Biochemistry, Molecular Biology and Biotechnology,University of Colombo RCV001270268 SCV001450483 pathogenic Squamous cell carcinoma of the head and neck criteria provided, single submitter case-control
Institute of Biochemistry, Molecular Biology and Biotechnology,University of Colombo RCV001270269 SCV001450484 pathogenic Colorectal cancer criteria provided, single submitter case-control
Department of Pediatrics,Memorial Sloan Kettering Cancer Center RCV000013173 SCV001478188 pathogenic Li-Fraumeni syndrome 1 2020-12-15 criteria provided, single submitter research
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 Breast neoplasm 2016-03-10 no assertion provided literature only
Mayo Clinic 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 Neoplasm of ovary 2018-12-01 no assertion criteria provided research
Institute of Medical Sciences, Banaras Hindu University RCV001255668 SCV001432233 pathogenic Lip and oral cavity carcinoma 2019-04-30 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000013173 SCV001551443 pathogenic Li-Fraumeni syndrome 1 no assertion criteria provided clinical testing The TP53 p.Arg175His variant was identified in 14 of 2378 proband chromosomes (frequency: 0.006) from individuals or families with Li Fraumeni syndrome, breast, ovarian and/or colon cancer (Walsh 2011, Melhem-Bertrandt 2012, Wong 2006, Bougeard 2008, Damineni 2014). This variant has also been identified in a child diagnosed with adrenocortical carcinoma at 6 months of age (Choong 2012) and a family that includes two individuals diagnosed with childhood sarcomas and four individuals diagnosed with brain tumours (Varley 1995). The variant was identified in dbSNP and ClinVar (classified as pathogenic by GeneDx, Invitae, Ambry Genetics, and 8 other submitters) . The variant was identified in control databases in 1 of 251276 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (non-Finnish) population in 1 of 113600 chromosomes (freq: 0.000009), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The R175 residue is a mutation hotspot and results in a structurally unstable, unfolded p53 protein (Xu 2014). The R175H variant has been shown to confer oncogenic gain of function to the p53 protein by multiple studies (Petitjean 2007, Capponcelli 2005), which is hypothesized to occur via the increased activation of the c-Met receptor tyrosine kinase and/or the inactivation of the ATM-dependent DNA damage response, resulting in a defective G2/M checkpoint (Grugan 2013, Liu 2010). The p.Arg175 residue is conserved across mammals and other organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the His variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
University Health Network,Princess Margaret Cancer Centre RCV001527463 SCV001738476 pathogenic Familial cancer of breast 2021-03-19 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000213054 SCV001808819 pathogenic not provided no assertion criteria provided clinical testing

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