Submissions for variant NM_000546.6(TP53):c.800G>A (p.Arg267Gln)

gnomAD frequency: 0.00001  dbSNP: rs587780075

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000205433	SCV001429619	uncertain significance	Li-Fraumeni syndrome	2020-08-11	reviewed by expert panel	curation	This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3). This variant has been reported in 2 probands meeting Chrompret criteria (PS4_Supporting; PMID:25584008, internal laboratory contributor). Transactivation assays show partially functional variant according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting; PMID: 12826609, 30224644). In summary, the clinical significance of TP53 c.800G>A (p.Arg267Gln) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Expert Panel: PP3, PS4_Supporting, BS3_Supporting.
GeneDx	RCV000213058	SCV000149646	uncertain significance	not provided	2016-02-18	criteria provided, single submitter	clinical testing	This variant is denoted TP53 c.800G>A at the cDNA level, p.Arg267Gln (R267Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has been reported in an affected child from a Li-Fraumeni syndrome family, co-occurring with two other TP53 variants (Quesnel 1999). This variant has also been identified in a woman who had breast cancer at age 49 and a family history of breast, ovarian, and colon cancers; however, the variant was also identified in a 74-year-old unaffected relative (Prosser 1992). TP53 Arg267Gln was reported in a child with adrenocortical carcinoma; however the child's mother also carried the variant and was unaffected, and there was no reported family history of cancer (Wasserman 2015). In addition, this variant has been identified in at least two colon cancer cases (Kandioler 2015). This variant has demonstrated mixed results in studies assessing transactivation activity, and although it has been shown to be deficient in colony reduction and have significantly reduced growth suppressive ability, it has yielded TP53 expression levels comparable to wild type (Quesnel 1999, Jordan 2010, Monti 2011, Wasserman 2015).Population frequency data is not available for TP53 Arg267Gln in the NHLBI Exome Sequencing Project or 1000 Genomes. Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. TP53 Arg267Gln occurs at a position that is not conserved and is located within the region of interaction with E4F1 (UniProt). One published splicing model predicts that TP53 Arg267Gln introduces a new splice acceptor site (Kouidou 2009), however internal splicing models are inconsistent regarding the effect of this variant on splicing. Protein-based 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 Arg267Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000115737	SCV000185134	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-20	criteria provided, single submitter	clinical testing	The p.R267Q variant (also known as c.800G>A) is located in coding exon 7 of the TP53 gene. This alteration results from a G to A substitution at nucleotide position 800. The arginine at codon 267 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been described several times in conjunction with a second TP53 alteration, p.R156H, in patients meeting LFS criteria, or with LFS spectrum tumors (Quesnel et al. Oncogene. 1999 Jul 8;18(27):3970-8; DiNardo CD et al. Clin Lymphoma Myeloma Leuk. 2016 Jul;16(7):417-428.e2; Pearlman R et al. JAMA Oncol. 2017 Apr 1;3(4):464-471; Swaminathan M et al. Cold Spring Harb Mol Case Stud, 2019 02;5:). This alteration was also described in a patient with breast cancer at 49 years of age, and a family history of lung, breast and ovarian cancer, however, the alteration was also identified in a 74 year old unaffected family member (Prosser et al. Br J Cancer. 1992 Apr;65(4):527-8). In addition, this alteration was detected in a child with adrenal cortical carcinoma, as well as the child's unaffected mother (Wasserman JD et al. J Clin Oncol. 2015 Feb 20;33(6):602-9). Yeast based functional studies describe this alteration as having partially functional transactivation capacity with wide ranging values from as low as 16% to greater than 100% of wild type activity for activation of various downstream targets (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti P et al. Mol Cancer Res. 2011. 9(3):271-279; Wasserman JD et al. J Clin Oncol. 2015 Feb 20;33(6):602-9). Growth suppression or colony reduction assays show activity similar to wild type (Wasserman JD et al. J Clin Oncol. 2015 Feb 20;33(6):602-9; Kotler E et al. Mol. Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Based on internal structural analysis, this variant is not destabilizing, and does not impact any known motifs or protein-protein interfaces (Cho Y et al., Science 1994 Jul; 265(5170):346-55). This alteration has been seen numerous times in our laboratory; several times in unaffected individuals, and never in a case of classic Li Fraumeni syndrome. Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205433	SCV000260755	uncertain significance	Li-Fraumeni syndrome	2024-01-17	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 267 of the TP53 protein (p.Arg267Gln). This variant is present in population databases (rs587780075, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 1562462, 9667734, 10435620, 17606709, 25584008, 27210295, 30709875; Invitae). ClinVar contains an entry for this variant (Variation ID: 127823). 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 does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Color Diagnostics, LLC DBA Color Health	RCV000115737	SCV000686776	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 267 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 this variant to have a partial defect in transcriptional transactivation activity (PMID: 12826609, 17606709, 20407015, 21343334, 25584008), partial to normal function in human cell growth suppression assays (PMID: 10435620, 25584008, 30224644) and normal function in human cell proliferation assays (PMID: 29979965). This variant has been reported in individuals with suspected Li-Fraumeni syndrome (PMID: 9667734, 10435620, 30709875, 27210295), breast cancer (PMID: 1394133, 1562462, 26225655, 28135048, 29875428, 31060593), colorectal cancer (PMID: 27978560), ovarian cancer (PMID: 16229746), lung cancer (PMID: 28843361), adrenocortical carcinoma (PMID: 25584008), and lymphoma (PMID: 32504211) in the literature. However it has also been found in controls and unaffected family members (PMID: 1562462, 33471991). This variant has been identified in 3/249356 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Counsyl	RCV000662441	SCV000784905	uncertain significance	Li-Fraumeni syndrome 1	2017-02-02	criteria provided, single submitter	clinical testing
Division of Medical Genetics, University of Washington	RCV000662441	SCV001434316	uncertain significance	Li-Fraumeni syndrome 1	2020-03-17	criteria provided, single submitter	clinical testing	This variant has been reported in a child who developed multiple primary cancers during childhood; however, this variant was inherited on the same haplotype as another variant, p.Arg156His (Quesnel 1999). This variant was also observed in a woman with breast cancer at age 49 who had a family history of breast, ovarian, and lung cancers occurring in relatives at mostly older ages (Prosser 2012). An experimental study found that the this variant retained transactivation capacity similar to wild type when exposed to high levels of galactose (Jordan 2015). This variant has an allele frequency of 0.00001203 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico tools evaluating evolutionary conservation and impact on protein structure and function suggest that this variant may have a deleterious effect. Therefore, we interpret this as a variant of uncertain significance. PM2; PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001358724	SCV001554563	uncertain significance	not specified	2021-03-22	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.800G>A (p.Arg267Gln) results in a 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 1.2e-05 in 249356 control chromosomes. c.800G>A has been reported in the literature in individuals suspected to be affected with Li-Fraumeni Syndrome (e.g. Rines_1998, Quesnel_1999, DiNardo_2016, Swaminathan_2019). However, these reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome, as the variant was detected along with at least one additional TP53 variant of uncertain significance. To our knowledge, no co-segregation studies for the p.Arg267Gln variant in isolation in Li-Fraumeni families have been reported. The variant has also been detected in individuals with other cancer phenotypes, including individuals with breast cancer and adrenocortical carcinoma in which the variant was also found in unaffected family members, suggesting a lack of segregation with disease (e.g. Prosser_1992, Wasserman_2015). The IARC database reports the variant as being partially-functional based on overall transcription activity (TA) on eight different promoters as measured in yeast assays by Kato et al, 2003. These findings have been corroborated by other assays assessing transcriptional activity in yeast, showing a partial reduction in residual transcriptional activity in cells with the variant (e.g. Quesnel_1999, Jordan_2010, Monti_2011). However, an assay using a luciferase-reporter for TP53 activity in human cells lines found activity levels that exceeded wild-type and only mild affects on colony growth compared to wild-type (e.g. Wasserman_2015). Seven other ClinVar submitters (evaluation after 2014), including one expert panel, have all cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000115737	SCV002532712	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-07	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000662441	SCV004017873	uncertain significance	Li-Fraumeni syndrome 1	2023-04-11	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV000205433	SCV004823765	uncertain significance	Li-Fraumeni syndrome	2023-06-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 267 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 this variant to have a partial defect in transcriptional transactivation activity (PMID: 12826609, 17606709, 20407015, 21343334, 25584008), partial to normal function in human cell growth suppression assays (PMID: 10435620, 25584008, 30224644) and normal function in human cell proliferation assays (PMID: 29979965). This variant has been reported in individuals with suspected Li-Fraumeni syndrome (PMID: 9667734, 10435620, 30709875, 27210295), breast cancer (PMID: 1394133, 1562462, 26225655, 28135048, 29875428, 31060593), colorectal cancer (PMID: 27978560), ovarian cancer (PMID: 16229746), lung cancer (PMID: 28843361), and adrenocortical carcinoma (PMID: 25584008) and lymphoma (PMID: 32504211) in the literature. However it has also been found in controls and unaffected family members (PMID: 1562462, 33471991). This variant has been identified in 3/249356 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV004567016	SCV005054323	uncertain significance	Adrenocortical carcinoma, hereditary	2024-03-19	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358329	SCV001554031	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The TP53 p.Arg267Gln variant was identified in 16 of 11062 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer, lung cancer, adrenocortical carcinoma, sarcoma, and/or Li Fraumeni syndrome (DiNardo 2016, Wasserman 2015, Arcand 2008, Petitjean 2007, Rines 1998). The variant was also identified in ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics, Color and Counsyl) and LOVD 3.0 (as affects function, not classified). The variant was identified in control databases in 3 of 249356 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6086 chromosomes (freq: 0.0002) and European (non-Finnish) in 2 of 112540 chromosomes (freq: 0.00002), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.Arg267 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Arg variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. Functional studies on this variant present conflicting results, such as decreased residual activity but increased transactivation in comparison to wild type (Wasserman 2015, Monti 2011, Jordan 2010). Another study suggests that this variant may result in the creation of a new splice acceptor site (Kouidou 2009). The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.