13-32340629-CTT-C
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000059.4(BRCA2):c.6275_6276del(p.Leu2092ProfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000691 in 1,606,550 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000074 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.862
Genes affected
BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 13-32340629-CTT-C is Pathogenic according to our data. Variant chr13-32340629-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 9318.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340629-CTT-C is described in Lovd as [Pathogenic]. Variant chr13-32340629-CTT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.6275_6276del | p.Leu2092ProfsTer7 | frameshift_variant | 11/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.6275_6276del | p.Leu2092ProfsTer7 | frameshift_variant | 11/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
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GnomAD3 genomes 0.0000263 AC: 4AN: 152172Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000370 AC: 9AN: 243532Hom.: 0 AF XY: 0.0000304 AC XY: 4AN XY: 131786
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:48Uncertain:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:19
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Oct 12, 2017 | This c.6275_6276del (p.Leu2092Profs*7) variant in exon 11 of the BRCA2 gene is a deletion of 2 nucleotides and is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. This particular variant (also known as 6503delTT) has been reported in multiple individuals affected with breast, ovarian, and prostate cancer (PMID: 8524414, 22009639, 21324516, 22006311, 20736950, 23199084). The c.6275_6276del (p.Leu2092Profs*7) variant in BRCA2 gene is classified as pathogenic (Atteeq Rehman 10-12-2017). - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2001 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jul 18, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Oct 16, 2013 | - - |
| Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Apr 22, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | May 27, 2024 | PVS1; PM5_PTC_Strong - |
| Pathogenic, criteria provided, single submitter | literature only | Counsyl | Feb 18, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 28, 2023 | This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in dozens of individuals affected with breast and/or ovarian cancer and is a common disease-causing mutation in the European population (PMID: 21324516, 23199084, 23479189, 24156927, 26026974, 29566657). This variant also has been detected in a breast cancer case-control meta-analysis in 30/60463 cases and 5/53461 unaffected individuals with odds ratio of 5.307 (95% CI 2.059 to 13.679) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000156). This variant has been identified in 10/274924 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Feb 14, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Jul 26, 2023 | The BRCA2 c.6275_6276del (p.Leu2092ProfsTer7) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay. This variant has been reported in several individuals with breast and/or ovarian cancer (PMID: 11359068, 21324516, 22006311, 22009639, 26026974, 26041759, 27153395, 29335925, 29566657). It has a maximum subpopulation frequency of 0.0059% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant is also known as 6503delTT in the literature. In summary, this variant meets criteria to be classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genologica Medica | Jan 01, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili | Aug 22, 2024 | Null variant (frame-shift) in gene BRCA2, predicted to cause NMD. Loss-of-function is a known mechanism of disease (PVS1).Combined evidence strength is Very Strong (score = 12).Very Strong: ClinVar classifies this variant as Pathogenic, 3 stars. Strong: LOVD classifies this variant as Pathogenic (PP5). GnomAD genomes homozygous allele count = 0 is less than 2 for AD/AR gene BRCA2,GnomAD exomes homozygous allele count = 0 is less than 2 for AD/AR gene BRCA2 (PM2).We observed this variant in a 37-year-old woman with malignant breast cancer and a family history of breast cancer. - |
| Pathogenic, no assertion criteria provided | case-control | Molecular Oncology, Hospital Universitario Central de Asturias (HUCA) | May 24, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
not provided Pathogenic:13Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 04, 2020 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in multiple individuals with a personal or family history consistent with pathogenic variants in this gene (Wooster 1995, Edwards 2010, Walsh 2011, Zhang 2011, Bayraktar 2012, Higgs 2015); Also known as 6503delTT; This variant is associated with the following publications: (PMID: 16644204, 26026974, 20002770, 22460208, 10782928, 17850627, 10090482, 15131399, 28392550, 26295337, 29566657, 30630528, 30267214, 24830819, 26041759, 22009639, 22006311, 21324516, 20736950, 8524414, 26843898, 25330149, 16616110, 21993507, 17636422, 26586665, 25884701, 20104584, 14984974, 24156927, 23479189, 20859677, 11039575, 9585608, 9792861, 11453973, 11359068, 10486320, 16905680, 15689453, 17591843, 9537231, 16079000, 11179017, 27225637, 27356891, 28127413, 28301456, 27836010, 27153395, 25085752, 28918466, 12955716, 12698193, 9585613, 12161611, 10227398, 8896551, 23199084, 11597388, 29335925, 29422015, 29915322, 29909963, 30720243, 30322717, 30093976, 31090900, 30612635, 29945567, 32255556, 29625052, 31447099) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 24, 2022 | PP5, PM2, PS4_moderate, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 25, 2018 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 16, 2023 | This variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in individuals with hereditary breast and ovarian cancer (PMID: 27153395 (2016), 11359068 (2001), 12955716 (2003), 21324516 (2011), 22006311 (2011), 22009639 (2012), 23199084 (2010), 26026974 (2015), 26041759 (2015), 29566657 (2018), 29625052 (2018), 8524414 (1995)), male breast cancer (PMID: 29335925(2018)) and prostate cancer (PMID: 20736950 (2010), 29915322 (2018)). In a large scale breast cancer association study, the variant was observed among the breast cancer cases as well as in unaffected individuals (PMID: 33471991 (2021)). The frequency of this variant in the general population, 0.000081 (4/49646 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 18, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Jun 17, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 28, 2018 | The BRCA2 c.6275_6276delTT; p.Leu2092fs variant (rs11571658), also known as 6503delTT in traditional nomenclature, is reported in multiple individuals affected with breast, ovarian, or prostate cancer (Bayraktar 2012, de Juan 2015, Edwards 2010, Walsh 2011, Wooster 1995, Zhang 2011). This variant is reported as pathogenic by numerous laboratories in ClinVar (Variation ID: 9318), and it is found in the general population with a low overall allele frequency of 0.004% (10/274924 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting two nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Bayraktar S et al. Predictive factors for BRCA1/BRCA2 mutations in women with ductal carcinoma in situ. Cancer. 2012 Mar 15;118(6):1515-22. de Juan I et al. BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study. Fam Cancer. 2015 Dec;14(4):505-13. Edwards SM et al. Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer. 2010 Sep 7;103(6):918-24. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7. Wooster R et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995 Dec 21-28;378(6559):789-92. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):353-7. - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | BRCA2: PVS1, PM2, PS4:Moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Leu2092Profs*7) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs11571658, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 8524414, 20736950, 21324516, 22006311, 22009639, 23199084). It is commonly reported in individuals of European ancestry (PMID: 23199084). This variant is also known as 6503delTT. ClinVar contains an entry for this variant (Variation ID: 9318). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health | Aug 06, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 08, 2019 | The p.Leu2092ProfsX7 variant in BRCA2 has been reported >100 individuals with BRCA2-associated cancer (Breast Information Core Database (BIC)); Bayraktar 2012, de Juan 2015, Edwards 2010, Fostira 2018, Mijuskovic 2018, Walsh 2011, Wang 2018, Whitworth 2018, Wooster 1995, Zhang 2011). In addition, the p.Leu2080X variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282422.1) and has been suggested to be a European founder mutation (Janavicius 2010). This variant has been identified in 0.005% (6/124234) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org. It is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2092 and leads to a premature termination codon 7 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PS4, PM2. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency | Apr 18, 2017 | - - |
| Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 22, 2016 | Variant summary: The BRCA2 c.6275_6276delTT (p.Leu2092Profs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.p.N2135fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/120912 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in numerous Br/Ov cancer patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Pathology and Molecular Medicine, Queen's University | Apr 20, 2017 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 24, 2021 | The c.6275_6276delTT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 2 nucleotides between positions 6275 and 6276, causing a translational frameshift with a predicted alternate stop codon (p.L2092Pfs*7). This mutation has been detected in multiple individuals with breast and/or ovarian cancer (Khitto G et al. Hum. Hered. 2001;52:55-8; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Walsh T et al. Proc. Natl. Acad. Sci. USA. 2011 Nov;108:18032-7; Bayraktar S et al. Cancer. 2012 Mar;118:1515-22; Higgs JE et al. J. Med. Genet. 2015 Sep;52:642-5; de Juan I et al. Fam. Cancer. 2015 Dec;14:505-13; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-817; Fostira F et al. Breast Cancer Res. Treat. 2018 May;169:105-113; Wang YA et al. BMC Cancer. 2018 03;18:315). Of note, this alteration is also designated as 6503delTT in some published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 03, 2023 | This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in dozens of individuals affected with breast and/or ovarian cancer and is a common disease-causing mutation in the European population (PMID: 21324516, 23199084, 23479189, 24156927, 26026974, 29566657). This variant also has been detected in a breast cancer case-control meta-analysis in 30/60463 cases and 5/53461 unaffected individuals with odds ratio of 5.307 (95% CI 2.059 to 13.679) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000156). This variant has been identified in 10/274924 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | research | Academic Department of Medical Genetics, University of Cambridge | Jan 26, 2018 | Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. - |
Breast and/or ovarian cancer Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Aug 18, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 06, 2023 | - - |
Familial cancer of breast Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 10, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Oct 01, 2024 | Criteria applied: PVS1,PM5_STR - |
BRCA2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 28, 2024 | The BRCA2 c.6275_6276delTT variant is predicted to result in a frameshift and premature protein termination (p.Leu2092Profs*7). This variant, also known as c.6503delTT and rs11571658 in the literature, has been reported in individuals with breast and ovarian cancer (see, for example, Bayraktar et al. 2012. PubMed ID: 22009639; Table S1, Carter et al. 2018. PubMed ID: 30322717; de Juan et al. 2015. PubMed ID: 26026974), pancreatic cancer (Young et al. 2018. PubMed ID: 29945567), and prostate cancer (Table S3, Darst et al. 2021. PubMed ID: 32853339). This variant is reported in 0.0059% of alleles in individuals of Latino descent in gnomAD and is classified as pathogenic in the ClinVar database by several other clinical laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/9318/). Taken together, this variant is classified as pathogenic. - |
Endometrial carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Feb 21, 2023 | - - |
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