chr17-7673773-G-A
Variant names:
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PP3BS2BS3PM5_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.847C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 283(p.Arg283Cys). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; SCV000183772.8). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.33; Align GVGD = Class 55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). Another missense variant (c.848G>C, p.Arg283Pro) (ClinVar Variation ID: 486555), in the same codon have been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications.(PM5_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni Syndrome. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, PP3, PM5_Supporting. (Bayesian Points: -6; VCEP specifications version 2.0; 7/24/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000457/MONDO:0018875/009
Frequency
Genomes: 𝑓 0.000085 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000068 ( 0 hom. )
Consequence
TP53
NM_000546.6 missense
NM_000546.6 missense
Scores
10
4
5
Clinical Significance
Conservation
PhyloP100: 4.69
Genes affected
TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
PM5
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
BS2
For more information check the summary or visit ClinGen Evidence Repository.
BS3
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000855 AC: 13AN: 152100Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000716 AC: 18AN: 251440Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135894
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GnomAD4 exome AF: 0.0000684 AC: 100AN: 1461880Hom.: 0 Cov.: 33 AF XY: 0.0000770 AC XY: 56AN XY: 727244
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GnomAD4 genome 0.0000855 AC: 13AN: 152100Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4AN XY: 74312
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ClinVar
Significance: Likely benign
Submissions summary: Pathogenic:1Uncertain:10Benign:10Other:2
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3Benign:2
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 06, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 03, 2020 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Mar 05, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 27, 2022 | - - |
not specified Uncertain:2Benign:2Other:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 17, 2017 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 31, 2019 | 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. - |
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 28, 2025 | 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. The observed variant frequency is approximately 1.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05).c.847C>T has been reported in the literature in patients with chronic lymphocytic leukemia, 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, Keller_2004, Manoukian_2007, Melhem-Bertrandt_2012, Schulz_2012, Mitchell_2013, Wang_2013, Yurgelun_2015, Mai_2017, Momozawa_2018, Young_2018, Abe_2019, Tsaousis_2019, Rodriguez-Balada_2020, Shin_2020). Manoukian et al (2007) reported one patient who was affected with metachronous breast cancers and a subsequent leiomyosarcoma and carried TP53 c.847C>T variant along with a pathogenic BRCA2 variant (p.Arg2394X); however TP53 c.847C>T did not segregate with disease in the patients family, as it was absent in an astrocytoma patient. Lack of co-segregation with disease was also evident in the families of two probands affected with breast cancer (Fostira_2020) and one proband affected with glioblastoma multiforme who also carried a pathogenic MLH1 variant (c.333_334delTC, p.His112CysfsX9) depicted by the authors as the main cause of cancer (Stajkovska_2019). Functional studies provide conflicting results ranging from no defect (human cell line) to partially defective in yeasts (Monti_2011, Pekova_2011, Jagosova_2012). In addition, the IARC database indicates the variant to be functional based on overall transcription activity (TA) on eight different promoters as measured in yeast assays by Kato et al (2003). ClinVar contains an entry for this variant (Variation ID: 127824). Based on the evidence outlined above, the variant was classified as likely benign. - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Mar 04, 2025 | - - |
not provided Benign:3Other:1
| Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 22, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 27, 2020 | 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) - |
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | 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. - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2025 | TP53: PM5:Supporting, BS3:Supporting, BS2 - |
Li-Fraumeni syndrome Uncertain:1Benign:2
| Uncertain significance, criteria provided, single submitter | research | University of Washington Department of Laboratory Medicine, University of Washington | Mar 28, 2018 | 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. - |
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2025 | - - |
| Likely benign, reviewed by expert panel | curation | ClinGen TP53 Variant Curation Expert Panel, ClinGen | Aug 05, 2024 | The NM_000546.6: c.847C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 283(p.Arg283Cys). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; SCV000183772.8). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.33; Align GVGD = Class 55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). Another missense variant (c.848G>C, p.Arg283Pro) (ClinVar Variation ID: 486555), in the same codon have been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications.(PM5_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni Syndrome. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, PP3, PM5_Supporting. (Bayesian Points: -6; VCEP specifications version 2.0; 7/24/2024) - |
Li-Fraumeni syndrome 1 Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Aug 19, 2015 | - - |
Neoplasm of stomach Pathogenic:1
| Likely pathogenic, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Malignant tumor of breast Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Malignant glioma Uncertain:1
| Uncertain significance, criteria provided, single submitter | research | Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital | - | - - |
Choroid plexus papilloma;C0235974:Carcinoma of pancreas;C0346153:Familial cancer of breast;C0346629:Colorectal cancer;C0585442:Bone osteosarcoma;C1835398:Li-Fraumeni syndrome 1;C1859972:Adrenocortical carcinoma, hereditary;C2239176:Hepatocellular carcinoma;C2750850:Glioma susceptibility 1;C2931822:Nasopharyngeal carcinoma;C3553606:Basal cell carcinoma, susceptibility to, 7;C4748488:Bone marrow failure syndrome 5 Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 17, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T;T;T;T;.;.;.;T;T;.;T;T;T;T;T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
.;.;.;.;.;.;.;.;L;.;L;L;L;.;.;L;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL
Pathogenic
Sift
Pathogenic
D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.089, 0.034, 1.0
.;.;.;.;.;.;.;.;B;.;B;D;B;.;.;B;.;.;.
Vest4
MVP
MPC
0.43
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at