Submissions for variant NM_000059.4(BRCA2):c.7558C>T (p.Arg2520Ter)

gnomAD frequency: 0.00001  dbSNP: rs80358981

Total submissions: 33

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077405	SCV000282445	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Invitae	RCV000045244	SCV000073257	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV000162645	SCV000213082	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-17	criteria provided, single submitter	clinical testing	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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210182	SCV000266045	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-11-20	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000045244	SCV000271333	pathogenic	Hereditary breast ovarian cancer syndrome	2019-04-24	criteria provided, single submitter	clinical testing	The p.Arg2520X variant in BRCA2 has been reported in >40 individuals with BRCA2-associated cancers (Hàkansson 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.
GeneDx	RCV000217859	SCV000278874	pathogenic	not provided	2020-02-20	criteria provided, single submitter	clinical testing	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)
Color Diagnostics, LLC DBA Color Health	RCV000162645	SCV000292167	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000217859	SCV000296742	pathogenic	not provided	2020-01-16	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA2 protein synthesis. This variant has been reported in several patients with breast and/or ovarian cancer (PMID: 28194609 (2017), 25863477 (2015), 22009639 (2012), 21913181 (2012), 21990299 (2011), 14981104 (2004), 9150154 (1997)). This variant has also been reported in a limited number of cases of 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, 0.000029 (1/34580 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077405	SCV000327682	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000077405	SCV000489082	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-08-16	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000045244	SCV000588114	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000217859	SCV000602766	pathogenic	not provided	2022-04-12	criteria provided, single submitter	clinical testing	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.
Department of Medical Genetics, Oslo University Hospital	RCV000077405	SCV000605679	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045244	SCV000695078	pathogenic	Hereditary breast ovarian cancer syndrome	2016-09-15	criteria provided, single submitter	clinical testing	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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077405	SCV000744521	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000077405	SCV000839930	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-01-14	criteria provided, single submitter	clinical testing	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170971	SCV001333631	pathogenic	Breast and/or ovarian cancer	2023-02-03	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000217859	SCV001447668	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000217859	SCV001450194	pathogenic	not provided	2016-09-14	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000217859	SCV001714435	pathogenic	not provided	2019-11-14	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
Revvity Omics, Revvity	RCV000217859	SCV002019075	pathogenic	not provided	2022-10-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000217859	SCV002497659	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PM2, PM5, PS4:Moderate
Sema4, Sema4	RCV000162645	SCV002531873	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-19	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000217859	SCV004027474	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002250522	SCV004211797	pathogenic	Familial cancer of breast	2023-10-29	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077405	SCV000109202	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2013-03-14	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077405	SCV000147121	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148425	SCV000190124	pathogenic	Breast neoplasm	2014-06-01	no assertion criteria provided	research
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000045244	SCV000587899	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353932	SCV000592123	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000077405	SCV000733301	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV002250522	SCV002520833	pathogenic	Familial cancer of breast		no assertion criteria provided	literature only
BRCAlab, Lund University	RCV000077405	SCV002588909	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing