Total submissions: 26
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000226273 | SCV000285213 | uncertain significance | Li-Fraumeni syndrome | 2020-01-12 | 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. |
Gene |
RCV000767028 | SCV000293522 | uncertain significance | not provided | 2018-02-22 | criteria provided, single submitter | clinical testing | This variant is denoted TP53 c.845G>A at the cDNA level, p.Arg282Gln (R282Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant was observed in a patient with neuroblastoma and was reportedly inherited from one of her parents, but the family history was not suggestive of Li-Fraumeni syndrome (Chompret 2000). Functional analyses have found that TP53 Arg282Gln results in varied transactivation or repression abilities across p53 responsive elements (Andreotti 2011, Resnick 2003, Monti 2011, Campomenosi 2001), and this variant is reported as having partially functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Arg282Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. TP53 Arg282Gln occurs at a position that is not conserved and is located in the DNA binding domain (Bode 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether TP53 Arg282Gln is pathogenic or benign. We consider it to be a variant of uncertain significance. |
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, |
RCV000235474 | SCV000605422 | likely pathogenic | not specified | 2016-11-07 | criteria provided, single submitter | clinical testing | |
Integrated Genetics/Laboratory Corporation of America | 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, |
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 | RCV000492420 | SCV000903415 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-03-25 | criteria provided, single submitter | clinical testing | |
Database of Curated Mutations |
RCV000428909 | SCV000509612 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439593 | SCV000509613 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000422340 | SCV000509614 | likely pathogenic | Squamous cell carcinoma of the skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429554 | SCV000509615 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438489 | SCV000509616 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421276 | SCV000509617 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431918 | SCV000509618 | likely pathogenic | Ovarian Serous Cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000442318 | SCV000509619 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423658 | SCV000509620 | likely pathogenic | Adenocarcinoma of prostate | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000434324 | SCV000509621 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000442471 | SCV000509622 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427734 | SCV000509623 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000433180 | SCV000509624 | likely pathogenic | Non-Hodgkin lymphoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
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 |
RCV000426667 | SCV000509626 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437335 | SCV000509627 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000418376 | SCV000509628 | likely pathogenic | Adenocarcinoma of stomach | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425549 | SCV000509629 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436164 | SCV000509630 | likely pathogenic | Renal cell carcinoma, papillary, 1 | 2016-05-31 | no assertion criteria provided | literature only |