ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7558C>T (p.Arg2520Ter) (rs80358981)

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Total submissions: 22
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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 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 and ovarian cancer syndrome 2018-12-28 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. This variant is present in population databases (rs80358981, ExAC 0.005%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 9150154, 14981104, 21990299, 22009639, 23242139, 24959366, 25863477, 20104584, 16284991), and an individual with pancreatic cancer (PMID: 24959366). This variant is also known as 7786C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 52353). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000162645 SCV000213082 pathogenic Hereditary cancer-predisposing syndrome 2017-08-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
University of Washington Department of Laboratory Medicine,University of Washington RCV000210182 SCV000266045 pathogenic Breast-ovarian cancer, familial 1 2015-11-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000045244 SCV000271333 pathogenic Hereditary breast and ovarian cancer syndrome 2015-07-30 criteria provided, single submitter clinical testing The p.Arg2520X variant in BRCA2 has been reported in >40 individuals with BRCA2- associated cancers (Hakansson 1997, Bayraktar 2012, Castera 2014, Schultheis 201 4, Breast Cancer Information Core (BIC) database), and segregated with associate d cancers in 2 affected relatives from 1 family. This variant has also been iden tified in 3/66376 European chromosomes by the Exome Aggregation Consortium (ExAC , http://exac.broadinstitute.org; dbSNP rs80358981). This nonsense variant leads to a premature termination codon at position 2520, which is predicted to lead t o a truncated or absent protein. Heterozygous loss of BRCA2 function is an estab lished disease mechanism in hereditary breast and ovarian cancer (HBOC). In summ ary, this variant meets criteria to be classified as pathogenic for HBOC in an a utosomal dominant manner based on the low frequency in controls, presence in aff ected individuals, and predicted impact to the protein.
GeneDx RCV000217859 SCV000278874 pathogenic not provided 2018-07-03 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.7558C>T at the cDNA level and p.Arg2520Ter (R2520X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also published as BRCA2 7786C>T using alternate nomenclature, has been reported in multiple individuals with breast, ovarian, and/or pancreatic cancer, many with family histories of breast and/or ovarian cancer (Hakansson 1997, Malander 2004, Pal 2005, Yang 2011, Bayraktar 2012, Schultheis 2014, Nakamura 2015, Wong-Brown 2015, Kwong 2016). We consider this variant to be pathogenic.
Color RCV000162645 SCV000292167 pathogenic Hereditary cancer-predisposing syndrome 2015-03-09 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000217859 SCV000296742 pathogenic not provided 2015-02-12 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077405 SCV000327682 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077405 SCV000489082 pathogenic Breast-ovarian cancer, familial 2 2016-08-16 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000045244 SCV000588114 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000045244 SCV000592123 pathogenic Hereditary breast and ovarian cancer syndrome 2015-04-08 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506897 SCV000602766 pathogenic not specified 2016-08-19 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000077405 SCV000605679 pathogenic Breast-ovarian cancer, familial 2 2015-07-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000045244 SCV000695078 pathogenic Hereditary breast and 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.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000077405 SCV000744521 pathogenic Breast-ovarian cancer, familial 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 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.
Sharing Clinical Reports Project (SCRP) RCV000077405 SCV000109202 pathogenic Breast-ovarian cancer, familial 2 2013-03-14 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077405 SCV000147121 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148425 SCV000190124 pathogenic Neoplasm of the breast 2014-06-01 no assertion criteria provided research
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000045244 SCV000587899 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000077405 SCV000733301 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing

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