13-32356550-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000059.4(BRCA2):c.7558C>T(p.Arg2520*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000059.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.7558C>T | p.Arg2520* | stop_gained | 15/27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.7189C>T | p.Arg2397* | stop_gained | 15/27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.7558C>T | non_coding_transcript_exon_variant | 14/26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152204Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251188Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135746
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461890Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727244
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152204Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74356
ClinVar
Submissions by phenotype
not provided Pathogenic:11
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Sep 14, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 12, 2022 | The BRCA2 c.7558C>T; p.Arg2520Ter variant (rs80358981) has been described in individuals with breast, ovarian, pancreatic, prostate and testicular cancer (Hakansson 1997, Yang 2011, Schultheis 2014). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 52353) and observed in the general population at a low overall frequency of 0.0016% (4/245940 alleles) in the Genome Aggregation Database. This variant introduces a premature termination codon, 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 pathogenic. References: Hakansson S et al. Moderate frequency of BRCA1 and BRCA2 germ-line mutations in Scandinavian familial breast cancer. Am J Hum Genet. 1997;60(5):1068-78. Schultheis A et al. Squamous Cell Carcinoma of the Pancreas in a Patient with Germline BRCA2 Mutation-Response to Neoadjuvant Radiochemotherapy. Case Rep Oncol Med. 2014;2014:860532. Yang D et al. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA. 2011;306(14):1557-65. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg | Apr 30, 2024 | This variant has been identified by standard clinical testing. female patient with triple negativ breast cancer Selected ACMG criteria: Pathogenic (I):PP5;PM2;PVS1 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 20, 2020 | Nonsense 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; Observed in individuals with a personal and family history consistent with pathogenic variants in this gene (Hakansson 1997, Malander 2004, Pal 2005, Yang 2011, Bayraktar 2012, Schultheis 2014, Nakamura 2015, Wong-Brown 2015, Kwong 2016); Not observed at a significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 25525159, 25863477, 26315209, 26296701, 27067391, 28188963, 28008555, 29339979, 9150154, 24959366, 24249303, 21990299, 21913181, 20104584, 14981104, 14746861, 25682074, 27157322, 22009639, 25637381, 25985138, 25085752, 16284991, 28194609, 29433453, 28831036, 27989354, 28724667, 30050867, 29360550, 28993434, 30720863, 29446198, 30720243, 30706003, 30702160, 30322717, 32846166, 33646313, 31447099, 32853339, 31825140, 32719484, 32338768, 30787465, 33087929) - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jan 09, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 04, 2024 | The BRCA2 c.7558C>T (p.Arg2520*) variant causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in multiple individuals with breast and/or ovarian cancer (PMIDs: 36853301 (2023), 36171877 (2022), 35834759 (2022), 28194609 (2017), 25863477 (2015), 22009639 (2012), 21913181 (2012), 21990299 (2011), 14981104 (2004), 9150154 (1997)). This variant has also been reported in individuals with prostate cancer (PMID: 29433453 (2018)), pancreatic cancer (PMID: 24959366 (2014)) and biliary tract cancer (PMID: 29360550 (2018)). The frequency of this variant in the general population, 0.000026 (3/113554 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 14, 2019 | PVS1, PM2, PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | BRCA2: PVS1, PM2, PS4:Moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 17, 2022 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:10
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
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 | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Jul 01, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 16, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Mar 14, 2013 | - - |
Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Jan 14, 2018 | This c.7558C>T (p.Arg2520*) variant in exon 15 of the BRCA2 gene creates a premature translation termination codon and is predicted to result in loss of function through nonsense-mediated mRNA decay or by producing a truncated protein, which is a known disease mechanism for this gene. This variant has been reported in multiple hereditary breast and ovarian cancer patients (PMID: 9150154, 21990299, 22009639, 24959366, 25863477, 16284991, 25525159) and an individual with pancreatic cancer (PMID: 24959366). The c.7558C>T (p.Arg2520*) variant in the BRCA2 gene is classified as pathogenic. - |
Hereditary breast ovarian cancer syndrome Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 15, 2016 | Variant summary: The BRCA2 c.7558C>T (p.Arg2520X) 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. If a protein product is made, it is predicted to truncate the helical domain, nucleic acid-binding/OB-fold domain, tower domain, and oligonucleotide/oligosaccharide-binding 1 domain (via InterPro). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.7721G>A/p.Trp2574X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 3/120748 control chromosomes at a frequency of 0.0000248, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in many HBOC patients in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
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 | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 24, 2019 | The p.Arg2520X variant in BRCA2 has been reported in >40 individuals with BRCA2-associated cancers (Hà kansson 1997, Bayraktar 2012, Castéra 2014, Schultheis 2014, Breast Cancer Information Core (BIC) database), and segregated with associated cancers in 2 affected relatives from 1 family. This variant has also been identified in 3/113554 European chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population This nonsense variant leads to a premature termination codon at position 2520, which is predicted to lead to a truncated or absent protein. Heterozygous loss of BRCA2 function 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 based on the low frequency in controls, presence in affected individuals, and predicted impact to the protein. ACMG/AMP Criteria applied: PVS1, PS4, PM2_Supporting. - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Pathology and Molecular Medicine, Queen's University | Apr 20, 2017 | - - |
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.Arg2520*) 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 (rs80358981, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer and pancreatic cancer (PMID: 9150154, 14981104, 16284991, 20104584, 21990299, 22009639, 23242139, 24959366, 25863477). This variant is also known as 7786C>T. ClinVar contains an entry for this variant (Variation ID: 52353). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 09, 2024 | The p.R2520* pathogenic mutation (also known as c.7558C>T), located in coding exon 14 of the BRCA2 gene, results from a C to T substitution at nucleotide position 7558. This changes the amino acid from an arginine to a stop codon within coding exon 14. This mutation has been reported in multiple Hereditary Breast and Ovarian Cancer Syndrome (HBOC) families from various ethnic backgrounds (Håkansson S et al. Am J Hum Genet, 1997 May;60:1068-78; Adem C et al. Cancer, 2003 Jan;97:1-11; Malander S et al. Eur J Cancer, 2004 Feb;40:422-8; Rebbeck TR et al. J Clin Oncol, 2004 Mar;22:1055-62; Pal T et al. Cancer, 2005 Dec;104:2807-16; Borg A et al. Hum Mutat, 2010 Mar;31:E1200-40; Yang D et al. JAMA, 2011 Oct;306:1557-65; Litton JK et al. Cancer, 2012 Jan;118:321-5; Bayraktar S et al. Cancer, 2012 Mar;118:1515-22; Haiman CA et al. PLoS Genet, 2013 Mar;9:e1003419; Castéra L et al. Eur J Hum Genet, 2014 Nov;22:1305-13; Wong-Brown MW et al. Breast Cancer Res Treat, 2015 Feb;150:71-80; Kang E et al. Breast Cancer Res Treat, 2015 May;151:157-68; Lu C et al. Nat Commun. 2015 Dec 22;6:10086; Shirts BH et al. Genet Med, 2016 10;18:974-81; Donenberg T et al. Breast Cancer Res Treat, 2016 08;159:131-8; Maxwell KN et al. Nat Commun, 2017 08;8:319; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Zidekova D et al. Neoplasma;65:309-315; Arai M et al. J Hum Genet, 2018 Apr;63:447-457; Wardell CP et al. J. Hepatol., 2018 05;68:959-969; Wen WX et al. J Med Genet, 2018 02;55:97-103; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Kwong A et al. Oncotarget, 2018 Jan;9:7832-7843; Deng M et al. Int J Cancer, 2019 09;145:1517-1528; Manchana T et al. World J Clin Oncol, 2019 Nov;10:358-368). In one study, this variant was reported in 10/60,466 breast cancer cases as well as in 4/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been reported in patients with prostate, pancreatic, esophageal and renal cancers (Na R et al. Eur Urol, 2017 05;71:740-747; Ibrahim M et al. BMC Cancer, 2018 02;18:179; Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149; Wu Y et al. Eur Urol Oncol, 2020 04;3:224-230; Veyseh M et al. Front Oncol, 2018 Jul;8:259; Toss A et al. Cancers (Basel), 2019 Feb;11; Wolfe AR et al. Adv Radiat Oncol Sep;4:10-14; Ko JM et al. Int J Cancer, 2020 02;146:1042-1051; Hartman TR et al. Sci Rep, 2020 08;10:13518). This alteration has also been detected in cohorts of healthy individuals who underwent multigene panel testing (Grzymski JJ et al. Nat Med, 2020 08;26:1235-1239; Qin Z et al. J Med Genet, 2021 Sep;58:587-591). Of note, this alteration is also designated as 7786C>T in 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 | curation | Sema4, Sema4 | Sep 19, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 05, 2023 | This variant changes 1 nucleotide in exon 15 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in over 30 individuals and families affected with breast and ovarian cancer (PMID: 9150154, 14746861, 15131399, 16284991, 20104584. 21990299, 21913181, 25682074, 25863477, 26295337, 28724667, 28993434, 30287823, 33471991) and 4 unaffected carriers (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001041). This variant has been identified in 5/251188 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. - |
Familial cancer of breast Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 14, 2024 | - - |
Pathogenic, no assertion criteria provided | literature only | Center for Precision Medicine, Meizhou People's Hospital | - | - - |
Breast and/or ovarian cancer Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Feb 03, 2023 | - - |
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | - - |
BRCA2-related cancer predisposition Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 16, 2024 | The c.7558C>T variant in the BRCA2 gene is located on exon 15 and introduces a premature translation termination codon (p.Arg2520*), resulting in an absent or disrupted protein product. The variant has been reported in multiple unrelated individuals with breast/ovarian/prostate cancer (PMID: 34570441, 29534594, 28194609, 35834759, 36853301, 31467961, 36171877). Other frameshift/truncating variants in the same exon have been reviewed as pathogenic (p.Ala2513fs, p.Ala2526fs, ClinVar ID: 52350, 225751). Loss-of-function variants in the BRCA2 gene are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 52353) and reviewed by the expert panel. The variant is rare in general population according to gnomAD (5/251188 chromosomes). Therefore, the c.7558C>T (p.Arg2520*) variant in the BRCA2 gene has been classified as pathogenic. - |
Breast neoplasm Pathogenic:1
Pathogenic, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Malignant tumor of breast Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Arg2520X variant is identified in 2 out of 4418 proband chromosomes with unilateral and familial breast cancers, although it was not investigated in controls (Håkansson 1997, Borg 2010). It was listed in the dbSNP database as coming from a "clinical source" (ID#: rs80358981) with no frequency information available. However, this variant has been presented as a clinically important variant in the UMD (3 times) and the BIC (44 times) databases. The p.Arg2520X variant leads to a premature stop codon at position 2520, which is predicted to lead to a truncated or absent BRCA2 protein. Loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at