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

gnomAD frequency: 0.00001  dbSNP: rs28934578

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131301	SCV000186273	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-17	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 mutation occurs at a well-characterized mutation hotspot (codon 175) in the 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). This variant is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). Based on the supporting evidence, this alteration is interpreted as a disease-causing 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	2024-01-31	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 175 of the TP53 protein (p.Arg175His). This variant is present in population databases (rs28934578, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 8164043, 8825920, 16401470, 21761402, 22006311). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12374). Advanced modeling performed at Invitae incorporating data from internal and/or published 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: 12007217, 12826609, 15607980, 15607981, 20516128, 23263379, 24573247, 29979965, 30224644). 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, Mass General Brigham 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, part of Exact Sciences	RCV000213054	SCV000806241	pathogenic	not provided	2017-04-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002476956	SCV000894156	pathogenic	Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Bone osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma; Colorectal cancer; Bone marrow failure syndrome 5	2022-04-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131301	SCV000905051	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-26	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 175 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 have shown that this variant results in the loss of TP53 protein function (PMID: 12826609, 15607981, 23263379, 29979965, 30224644), causes chromosomal instability (PMID: 25059482), and promotes tumor cell invasion (PMID: 15607981, 23792586). In mouse models of Li-Fraumeni syndrome, this variant has also been shown to impair TP53 function and cause TP53-related tumors (PMID: 15607980, 15607981). This variant has been reported in individuals affected with Li-Fraumeni syndrome meeting classic or Chompret diagnostic criteria (PMID: 8164043 , 8825920, 16401470, 21761402, 23172776, 27374712, 27516001). This variant has been shown to segregate with disease in a 4-generation extended family affected with Li-Fraumeni syndrome (PMID: 8825920). This variant has been identified in 1/251276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
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
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000213054	SCV002011128	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000204931	SCV002074556	pathogenic	Li-Fraumeni syndrome	2022-01-07	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.524G>A (p.Arg175His) results in a non-conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251276 control chromosomes. c.524G>A has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome, including 2 families where the variant strongly segregated with disease (Varley_1995, Varley_1997, etc). These data indicate that the variant is very likely to be associated with disease. In vitro functional studies show that R175H results in decreased activation of Tp53 targets, and additionally confers a gain of function to Tp53, resulting in aberrant activation of gene transcription and enhanced cell migration (TP53 database, Yeudall_2012). Additional evidence from an animal model indicates that this variant contributes to a phenotype similar to tumorigenesis (including thymic tumors, sarcomas, peripheral lymphomas and germ-cell tumors) (Liu_2010). Ten ClinVar submitters have assessed this variant since 2014: all ten classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000131301	SCV002582493	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000013173	SCV002583153	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000013173	SCV004044216	pathogenic	Li-Fraumeni syndrome 1	2023-05-11	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID:8825920, 8118819, 7887414]. Functional studies indicate this variant impacts protein function [PMID: 14743206, 15607980]. This variant is expected to disrupt protein structure [PMID: 8023157, Myriad internal data].
Baylor Genetics	RCV003466854	SCV004206223	pathogenic	Adrenocortical carcinoma, hereditary	2023-10-06	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	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, 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
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000213054	SCV001906154	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000213054	SCV001959136	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162247	SCV002758490	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research