Submissions for variant NM_000546.6(TP53):c.845G>A (p.Arg282Gln)

dbSNP: rs730882008

Total submissions: 33

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226273	SCV000285213	uncertain significance	Li-Fraumeni syndrome	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 282 of the TP53 protein (p.Arg282Gln). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of TP53-related conditions (PMID: 10864200, 17606709, 26787237, 26976419, 32318955). ClinVar contains an entry for this variant (Variation ID: 237956). 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: 11429705, 11896595, 12826609, 12909720, 12917626, 15982667, 19913028, 21343334, 29979965). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000767028	SCV000293522	uncertain significance	not provided	2024-08-18	criteria provided, single submitter	clinical testing	Identified in individuals with breast cancer, neuroblastoma, prostate cancer, or other tumors (PMID: 10864200, 25980754, 26787237, 26976419, 29324801, 32318955, 33008098, 32885271, 34863587, 35534704); Published functional studies demonstrate partially functional transactivation and retained growth suppression activity (PMID: 11429705, 12826609, 12909720, 21343334, 30224644, 29979965); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21674059, 15982667, 18059157, 18555592, 11429705, 12909720, 24324553, 10864200, 12917626, 26787237, 26976419, 29324801, 27276561, 29126202, 27895058, 27463065, 29979965, 32560038, 17606709, 21343334, 11920959, 27346245, 18559976, 22361592, 27323394, 24603336, 19913028, 28821955, 30720243, 30840781, 32318955, 31447099, 30450585, 30327374, 30224644, 26585234, 26230955, 25952993, 23246812, 22915647, 22186996, 21519010, 20972454, 20407015, 19171880, 18453682, 16818505, 12826609, 11896595, 28638988, 28597078, 31588562, 30823914, 11782540, 28387325, 25980754, 27680515, 26619011, 27959731, 30352134, 29058119, 34863587, 35647242, 32885271, 38392212, 34273903, 30675318, 37937776, 33008098, 33574475, 15510160, 35534704, 38933650)
Ambry Genetics	RCV000492420	SCV000581106	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-21	criteria provided, single submitter	clinical testing	The p.R282Q variant (also known as c.845G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 845. The arginine at codon 282 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a family in which the proband was diagnosed with neuroblastoma at 1 year of age and the proband's maternal aunt was diagnosed with lymphoma at 44 years of age (Chompret A et al. Br. J. Cancer. 2000 Jun;82(12):1932-1937). Functional studies conducted in yeast have demonstrated partially reduced transactivation activity compared to wild type (Campomenosi P et al. Oncogene. 2001 Jun;20:3573-9; Shi XB et al. Prostate. 2002 Apr;51:59-72; IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100(14):8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-9). Studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). Additional studies in human Saos-2 cell lines showed gain of function properties such as upregulation of several promoters, growth in soft agar, and an increase in DNA synthesis (Shi XB et al. Prostate. 2002 Apr;51:59-72). Crystal structural analysis predict this alteration may cause destabilization of the protein (Tu C et al. Acta Crystallogr. D Biol. Crystallogr. 2008 May;64:471-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This alteration has been detected in the literature and numerous times in our laboratory, however, never in a case that meets classic Li-Fraumeni syndorme or Chompret criteria (Ambry internal data). Although this alteration has not been detected in individuals with Li-Fraumeni syndrome, we can not rule out the possibility that it is a low penetrance risk allele. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000235474	SCV000605422	likely pathogenic	not specified	2016-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000235474	SCV000697451	uncertain significance	not specified	2020-09-29	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.845G>A (p.Arg282Gln) results in a conservative amino acid change located in the 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 251444 control chromosomes (gnomAD). c.845G>A has been reported in the literature in individuals affected with a variety of cancers but not fulfilling the classic criteria of LFS or even the LFI (Li-Fraunemi Incomplete) criteria. In our review of the associated literature, the penetrance of Li-Fraumeni Syndrome (0.67) due to this variant appears to be lower than expected (0.8), therefore no conclusions can be drawn from these data. Specifically, this variant was observed in a patient with neuroblastoma and was reportedly inherited from one of her parents, but the family history (a female patient, diagnosed at age 1 with neuroblastoma, and a maternal aunt with lymphoma diagnosed at 44) was not suggestive of Li-Fraumeni syndrome (Chompret 2000). The variant has been also reported as germline variant in several other cancer patients, including lung-, breast-, prostate and colorectal cancer, but without strong evidence for causality (Meric-Bernstam_2016, Tung_2016, Monti_2007, Giri_2019, Stoltze_2018). In addition, in one of these reports a co-occurrence with another likely pathogenic variant has been reported (PALB2 exon 13 deletion; Giri_2019), providing supporting evidence for limited causality. Additional studies are needed to address the penetrance and cancer risks associated with TP53 pathogenic variation in patients outside LFS spectrum. Several publications reported experimental evidence evaluating an impact on protein function, and multiple yeast assays demonstrated that the variant decreased, but did not abolish the transactivation capacity of TP53 and has been reported as a partially deficient (PD) allele (e.g. Monti_2011, Andreotti_2011 , Resnick_2003, Shi_2002). On the other hand, further studies performed in yeast and in human cells, revealed that the variant could also result in a gain of function activity, by interfering with the function of other p53 family members and increasing the expression of genes involved in cell proliferation- and tumor formation (Monti_2003, Shi_2002, Cordani_2011). These data however do not allow unequivocal conclusions about the variant significance. Six other clinical diagnostic laboratories have submitted conflicting clinical-significance assements for this variant to ClinVar after 2014 (i.e. 4 calling it a VUS, while 2 classifying it as likely pathogenic). At-least two of these submissions reflect a re-evaluation from their original assessment in the pathogenic spectrum. Based on the overall evidence outlined above, the variant was re-classified from its initial assessment as Likely Pathogenic at our laboratory and has since retained its classification as a VUS-possibly pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000709768	SCV000840078	likely pathogenic	Li-Fraumeni syndrome 1	2017-09-25	criteria provided, single submitter	clinical testing	The c.845G>A (p.Arg282Gln) variant in the TP53 gene has been reported as a germline change in two related individuals with a family history of cancer (PMID: 17606709). This variant has also been reported in individuals affected with breast cancer, lung cancer and neuroblastoma (PMID: 26976419, 26787237, 10864200). Experimental studies have shown that this missense change affects TP53 protein structure and function (PMID: 15982667, 19913028). A different pathogenic missense substitution at this codon (p.Arg282Trp) has been reported in multiple cancer patients (PMID: 1565143, 21059199, 21305319, 21761402, 22672556, 11370630, 25584008) suggesting that the arginine residue is critical for TP53 protein. Based upon the above evidence, this c.845G>A, p.Arg282Gln variant is classified as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000492420	SCV000903415	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-14	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 282 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 no or partially disruptive effect of this variant on transactivation activity in yeast-based assays (PMID: 11429705, 11896595, 11920959, 12826609, 12909720, 12917626, 21343334) and no effect on the anti-proliferative function of TP53 protein in mammalian cell-based assays (PMID: 29979965, 30224644). This variant has been reported in an infant affected with neuroblastoma with history of lymphoma in her maternal aunt (PMID 10864200). This variant has been observed in an individual affected with lung cancer in his seventies, with family history of breast and prostate cancer in his siblings (PMID: 26787237). This variant has also been observed in individuals affected with breast cancer (PMID: 26976419) and glioneuronal tumor (PMID: 29058119), as well as in an individual affected with colorectal cancer with early-onset breast cancer history in her mother and maternal grandmother (PMID: 29324801). This variant has been identified in 1/251444 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same amino acid position (p.Arg282Trp, p.Arg282Pro) are considered to be disease-causing (ClinVar variation ID: 12364, 376659), suggesting that arginine at this position is important for protein function. However, the available clinical and functional evidence is insufficient to determine the role of the p.Arg282Gln variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Genetic Services Laboratory, University of Chicago	RCV000235474	SCV002065826	uncertain significance	not specified	2021-05-19	criteria provided, single submitter	clinical testing	DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.845G>A, in exon 8 that results in an amino acid change, p.Arg282Gln. This sequence change has been described in gnomAD with only one heterozygous individual from the Finnish sup-population (dbSNP rs730882008). The p.Arg282Gln change affects a highly conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Arg282Gln substitution appears to be damaging using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been reported in a female patient diagnosed at age one with neuroblastoma. This sequence change was reportedly inherited from one of her parents and the family history (a maternal aunt with lymphoma diagnosed at 44) was not highly suggestive of Li-Fraumeni syndrome (PMID:10864200). This variant has also been reported in individuals affected with breast cancer, lung cancer, and prostate cancer but without strong evidence for causality (PMID: 26976419, 26787237, 30450585). In one of the reported cases of prostate cancer, a likely pathogenic deletion in exon 13 of the PALB2 gene was also identified, providing supporting evidence for limited causality of the TP53 variant (PMID:30450585). This amino acid position is considered a TP53 mutation hotspot where several other amino acid changes have been reported in individuals and families with TP53-related cancers (p.Arg282Gly, p.rg282Pro, p.Arg282Leu, p.Arg282Trp) (PMIDs: 15850016, 27616075, 28975465, 1565143). Functional studies have shown no or partially disruptive effect of this variant on transactivation activity in yeast-based assays (PMID: 11429705, 11896595, 11920959, 12826609, 12909720, 12917626, 21343334) and no effect on the anti-proliferative function of TP53 protein in mammalian cell-based assays (PMID: 29979965, 30224644). In summary, the c.845G>A sequence change has been reported in the literature in individuals affected with a variety of cancers but not fulfilling classic Li-Fraumeni syndrome criteria. Additionally, functional evidences are inconclusive. Based on the overall available evidence, the clinical significance of the p.Arg282Gln in TP53 change remains unknown at this time and has been classified as variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV000767028	SCV002498236	uncertain significance	not provided	2022-03-01	criteria provided, single submitter	clinical testing	TP53: PM1, PS3:Supporting
Baylor Genetics	RCV000709768	SCV004040929	uncertain significance	Li-Fraumeni syndrome 1	2023-08-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003463657	SCV004206207	uncertain significance	Adrenocortical carcinoma, hereditary	2024-02-26	criteria provided, single submitter	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV003483584	SCV004231846	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-09	criteria provided, single submitter	curation	. According to the ClinGen ACMG TP53 v1.4.0 criteria we chose these criteria: PM1 (medium pathogenic): This rule can be applied to variants in hot spots (codons 175, 245, 248, 249, 273, 282), PP3 (supporting pathogenic): AGVGD: C35, BayesDEL:0.477696 Fortuno et al. 2019 high probabilty of pathogenicity (>99%), BS3 (supporting benign): Kato 2003: partially functional / Giacomelli 2018: unclassified / Kotler 2018: no LoF RFS score: -1,61029460421 [cutoff RFS score > −1.0 for LOF and RFS score < −1.0 for noLOF]
All of Us Research Program, National Institutes of Health	RCV000226273	SCV004823761	uncertain significance	Li-Fraumeni syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 282 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 no or partially disruptive effect of this variant on transactivation activity in yeast-based assays (PMID: 11429705, 11896595, 11920959, 12826609, 12909720, 12917626, 21343334) and no effect on the anti-proliferative function of TP53 protein in mammalian cell-based assays (PMID: 29979965, 30224644). This variant has been reported in an infant affected with neuroblastoma with history of lymphoma in her maternal aunt (PMID 10864200). This variant has been observed in an individual affected with lung cancer in his seventies, with family history of breast and prostate cancer in his siblings (PMID: 26787237). This variant has also been observed in individuals affected with breast cancer (PMID: 26976419) and glioneuronal tumor (PMID: 29058119), as well as in an individual affected with colorectal cancer with early-onset breast cancer history in her mother and maternal grandmother (PMID: 29324801). This variant has been identified in 1/251444 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same amino acid position (p.Arg282Trp, p.Arg282Pro) are considered to be disease-causing (ClinVar variation ID: 12364, 376659), suggesting that arginine at this position is important for protein function. However, the available clinical and functional evidence is insufficient to determine the role of the p.Arg282Gln variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Database of Curated Mutations (DoCM)	RCV000428909	SCV000509612	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439593	SCV000509613	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422340	SCV000509614	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429554	SCV000509615	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438489	SCV000509616	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421276	SCV000509617	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431918	SCV000509618	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442318	SCV000509619	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423658	SCV000509620	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434324	SCV000509621	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442471	SCV000509622	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427734	SCV000509623	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433180	SCV000509624	likely pathogenic	Non-Hodgkin lymphoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444806	SCV000509625	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426667	SCV000509626	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437335	SCV000509627	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418376	SCV000509628	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425549	SCV000509629	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436164	SCV000509630	likely pathogenic	Papillary renal cell carcinoma type 1	2016-05-31	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357626	SCV001553150	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The TP53 p.Arg282Gln variant was identified in 4 of 6032 proband chromosomes (frequency: 0.0007) from individuals or families with neuroblastoma, breast cancer, lung cancer, or Lynch syndrome (Chrompret 2000, Meric-Bernstam 2016, Tung 2016, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs730882008 as "With Likely pathogenic, Pathogenic allele"), ClinVar (2x as pathogenic by Invitae and Ambry Genetics; 2x as likely pathogenic by ARUP Laboratories and Integrated Genetics/Laboratory Corporation of America; and 1x as uncertain significance by GeneDx), Cosmic (37x in Skin, Bone, Hematopoietic and lymphoid tissue, Upper aerodigestive tract or Large intestine), and the IARC TP53 Database (identified 2x in germline and 30x as somatic; classified as partially functional). The variant was not identified in the GeneInsight-COGR or LOVD 3.0 databases. The variant was identified in control databases in 2 of 277176 chromosomes at a frequency of 0.000007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European Non-Finnish in 1 of 126670 chromosomes (freq: 0.000008) and Finnish in 1 of 25792 chromosomes (freq: 0.00004), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or South Asian populations. Multiple studies using a yeast functional reporter assay have classified this variant as loss of function and concluded that this variant does not possess dominant negative activity (Hassan 2008, Shi 2002). The p.Arg282 residue is conserved across mammals and other organisms, and 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Arg282Gln variant may impact the protein; this information alone is not predictive enough to assume pathogenicity. However, the residue is located in the DNA-binding domain of TP53 and the Arg282Gln variant has been shown to accelerate the protein unfolding rate, possibly facilitating loss of protein function (Butler 2005). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.