Submissions for variant NM_000546.5(TP53):c.845G>A (p.Arg282Gln) (rs730882008)

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000226273	SCV000285213	uncertain significance	Li-Fraumeni syndrome	2020-10-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 282 of the TP53 protein (p.Arg282Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two related individuals with a family history of cancer (PMID: 17606709), and individuals affected with breast cancer, lung cancer and neuroblastoma (PMID: 26976419, 26787237, 10864200). ClinVar contains an entry for this variant (Variation ID: 237956). A different missense substitution at this codon (p.Arg282Trp) has been determined to be pathogenic (Invitae), suggesting that the arginine residue might be critical for TP53 protein function. Experimental studies have shown this variant (p.Arg282Gln) only partially impairs the transcriptional transactivation activity of TP53 in yeast-based assays (PMID: 12826609, 21343334, 11429705, 12909720, 12917626, 11896595), and may affect the structural stability of the TP53 protein (PMID: 15982667, 19913028). The clinical significance of these findings is uncertain. 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	2020-11-24	criteria provided, single submitter	clinical testing	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; Identified in individuals with breast cancer, neuroblastoma, or other tumors (Chompret 2000, Yurgelun 2015, Meric-Bernstam 2016, Tung 2016, Stoltze 2018, Zeng 2020); Published functional studies demonstrate partially functional transactivation and retained growth suppression activity (Campomenosi 2001, Kato 2003, Resnick 2003, Monti 2011, Giacomelli 2018, Kotler 2018); 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, 30675318, 27959731, 30352134, 33008098, 29058119, 32885271)
Ambry Genetics	RCV000492420	SCV000581106	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-04	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 mutation 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 a TP53 mutation hotspot wherein two additional missense alterations have been reported (p.R282G and p.R282W); both of these alterations have been identified in Li-Fraumeni families (Toguchida J et al. N. Eng. J. Med. 1992 May;326(20):1301-8; Poli T et al. Tumori; 91:96-100; Ambry internal data). 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 Health, Inc	RCV000492420	SCV000903415	uncertain significance	Hereditary cancer-predisposing syndrome	2019-03-25	criteria provided, single submitter	clinical testing
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	Adenocarcinoma of prostate	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	Adenocarcinoma of stomach	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	Renal cell carcinoma, papillary, 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.