Submissions for variant NM_000546.6(TP53):c.847C>T (p.Arg283Cys)

gnomAD frequency: 0.00009  dbSNP: rs149633775

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000200641	SCV001142525	likely benign	Li-Fraumeni syndrome	2022-03-18	reviewed by expert panel	curation	This variant has a BayesDel score >0.16 and Align GVGD (Zebrafish) is Class 25 or higher (PP3). This variant has been reported in 3 probands meeting Chompret criteria (PS4_Supporting; internal laboratory contributor (SCV000183772.7). However, this variant has been observed in greater than 8 60+ year old females without a cancer diagnosis (BS2; internal laboratory contributors: SCV000183772.7, SCV000254640.10) and has been seen many times by VCEP lab contributors in individuals not meeting LFS criteria. Transactivation assays show retained function 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; PMID: 12826609, 30224644). The TP53 VCEP reviewed the conflicting evidence (PP3 and PS4_Supporting) and felt it did not override the Likely Benign classification in this case. In summary, the TP53 VCEP classified this variant as likely benign. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PS4_Supporting, PP3, BS3, BS2.
GeneDx	RCV000585912	SCV000149648	likely benign	not provided	2020-10-27	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22652532, 19367569, 17289876, 25527155, 21343334, no PMID, 15173255, 30224644, 29979965, 31016814, 23018556, 22710932, 17224268, 25980754, 23894400, 24728327, 21288114, 21512767, 25637381, 19558493, 21232794, 16487937, 19714488, 11040944, 26086041, 24868540, 12826609, 11793474, 8198984, 9865903, 11391594, 17727479, 28125078, 28861920, 15580553, 8203469, 29785153, 29300620, 21761402, 30840781, 31159747, 30374176, 29945567, 31786208, 31749828, 33300245, 32658383)
Ambry Genetics	RCV000115739	SCV000183772	likely benign	Hereditary cancer-predisposing syndrome	2020-09-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000200641	SCV000254640	likely benign	Li-Fraumeni syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000122178	SCV000272533	uncertain significance	not specified	2019-01-31	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg283Cys variant in TP53 has been reported in multiple individuals with cancer who did not meet Li-Fraumeni diagnostic criteria, and as a somatic variant in at least 7 tumors (Faille 1994, Diller 1995, Rugge 2000, Prescott 2001, Keller 2004, Libe 2007, Manoukian 2007, Ryu 2007, Pekova 2011, Melhem-Bertandt 2012, Schulz 2012, Boyault 2012, Mitchell 2013, Yurgelun 2015, Brohl 2017). It has also been identified in 17/129154 European chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein, though in vitro functional studies provide some evidence that the p.Arg283Cys variant may impact protein function (Monti 2011, Pekova 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg283Cys variant is uncertain.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000238755	SCV000297015	uncertain significance	Li-Fraumeni syndrome 1	2015-08-19	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000122178	SCV000597522	uncertain significance	not specified	2017-04-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115739	SCV000686778	likely benign	Hereditary cancer-predisposing syndrome	2022-05-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000122178	SCV000697452	uncertain significance	not specified	2019-11-11	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.847C>T (p.Arg283Cys) results in a non-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 7.2e-05 in 251440 control chromosomes (gnomAD). The observed variant frequency is approximately 2-folds over the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome (LFS) phenotype (4e-05), strongly suggesting that the variant is benign. c.847C>T has been reported in the literature in patients with CLL, early-onset colorectal cancer, breast cancer, gastric carcinoma, pancreatic, and brain tumor as a germline or somatic variant, but most of the patients did not fulfill LFS criteria (e.g. Gaidano_1994, Yurgelun_2015, Manoukian_2007, Keller_2004, Melhem-Bertrandt_2012, Mitchell_2013, Schulz_2012, Wang_2013, Abe_2019, Mai_2017, Momozawa_2018, Tsaousis_2019, Young_2018). In addition, one patient who was affected with metachronous breast cancers and a subsequent leiomyosarcoma carried TP53 c.847C>T variant and a pathogenic BRCA2 variant (p.Arg2394X); however TP53 c.847C>T did not segregate with disease in her family, as it was absent in an astrocytoma patient (Manoukian_2007). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Functional studies provide conflicting results ranging from no defect (human cell line) to partially defective in yeasts (Pekova_2011, Monti_2011, Jagosova_2012). In addition, the IARC database indicates the variant to be functional. Twelve ClinVar submissions (evaluation after 2014) cite the variant eleven times as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
GeneKor MSA	RCV000115739	SCV000822209	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000200641	SCV000886456	uncertain significance	Li-Fraumeni syndrome	2018-03-28	criteria provided, single submitter	research	The TP53 variant designated as NM_000546.5:c.847C>T (p.Arg283Cys) is classified as unlikely to cause fully penetrant Li-Fraumeni syndrome. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and gives a likelihood ratio of less than 0.005 to 1 (Thompson et al., 2013, PMID:12900794) in the context of Li-Fraumeni syndrome. This indicates that the TP53 variant is very unlikely to increase the risks of cancer to the extent reported in Li-Fraumeni syndrome. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity in the context of Li-Fraumeni syndrome. Additionally, the familial germline TP53 variant was detected in a family member's breast tumor tissue without evidence of loss of heterozygosity. It was unclear whether there was a second hit. The absence of loss of heterozygosity in the tumor may provide some evidence that the TP53 variant is more likely to be benign. There have been many reports this variant in patients with cancer. Although it is clear that this variant does not cause classic Li-Fraumeni syndrome, we cannot rule out the possibility that this variant does cause some increased risk for breast and other cancers. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000585912	SCV000889883	likely benign	not provided	2023-06-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000585912	SCV000892470	likely benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	TP53: PP3, PS4:Supporting, BS3:Supporting, BS2
Fulgent Genetics, Fulgent Genetics	RCV002477279	SCV000896672	likely benign	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	2022-05-17	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000238755	SCV001440887	uncertain significance	Li-Fraumeni syndrome 1	2019-01-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115739	SCV002532714	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-06	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000122178	SCV004242756	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
ITMI	RCV000122178	SCV000086393	not provided	not specified	2013-09-19	no assertion provided	reference population
CSER _CC_NCGL, University of Washington	RCV000148912	SCV000190658	likely pathogenic	Neoplasm of stomach	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357872	SCV001553463	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The TP53 p.Arg283Cys variant was identified in 14 of 16242 proband chromosomes (frequency: 0.0009) from individuals or families with gastric cancer, breast cancer, leiomyosarcoma, sarcoma, or colorectal cancer and was present in 2 of 23844 control chromosomes (frequency: 0.00008) from healthy individuals (Keller 2004, Manoukian 2007, Mitchell 2013, Momozawa 2018, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs149633775) as "With Likely pathogenic allele", ClinVar (classified as likely benign by one submitter; as uncertain significance by Invitae, GeneDx, Ambry Genetics and six other submitters; and as likely pathogenic by one submitter), Cosmic (22x in breast, endometrium, pancreatic and other tissues ), and LOVD 3.0 (3x). The variant was identified in control databases in 24 of 277184 chromosomes at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). The frequency of the variant in certain populations increases the likelihood that this is a low frequency, benign variant; it was observed in the following populations: African in 3 of 24034 chromosomes (freq: 0.0001), Other in 1 of 6466 chromosomes (freq: 0.0002), and European in 20 of 126682 chromosomes (freq: 0.0002), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. In vitro studies of the variant provide conflicting data: the variant demonstrated weakly temperature-dependent activity, partial deficiency of activity, or activity similar to wild type (Jagosove 2012, Pekova 2011, Monti 2011). The variant was identified in a family meeting criteria for HBOC and Li Fraumeni-like syndrome along with a pathogenic BRCA2 variant (c.7408A>T, p.R2394X). The p.Arg283 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the 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 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicts a greater than 10% difference in splicing. 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.
GenomeConnect - Invitae Patient Insights Network	RCV000585912	SCV001716320	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 08-08-2017 by 1197. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory.