ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1929del (p.Arg645fs) (rs80359316)

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Total submissions: 17
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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) RCV000031350 SCV000282366 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 RCV000195352 SCV000071939 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.Arg645Glufs*15) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with breast and prostate cancer (PMID: 17636422, 8988179, 20736950). Other studies have reported this variant as a common pathogenic variant in affected individuals of Northern European descent (PMID: 14757871, 23199084, 24312913). This variant is also known as 2157delG. ClinVar contains an entry for this variant (Variation ID: 37769). 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 RCV000131475 SCV000186462 pathogenic Hereditary cancer-predisposing syndrome 2018-03-12 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)
Michigan Medical Genetics Laboratories,University of Michigan RCV000031350 SCV000195966 pathogenic Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000043926 SCV000210719 pathogenic not provided 2018-08-27 criteria provided, single submitter clinical testing This deletion of one nucleotide is denoted BRCA2 c.1929delG at the cDNA level and p.Arg645GlufsX15 (R645EfsX15) at the protein level. The normal sequence, with the base that is deleted in brackets, is CTGT[delG]AAAAG. The deletion causes a frameshift, which changes an Arginine to a Glutamic Acid at codon 645, and creates a premature stop codon at position 15 of the new reading frame. BRCA2 c.1929delG, also denoted BRCA2 2157delG using alternate nomenclature, is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been observed in male and female breast cancer cases (Gayther 1997, Lalloo 2003, Evans 2008, Pritzlaff 2017), in men with prostate cancer (Edwards 2010, Castro 2013), and in individuals with pancreatic cancer (Showalter 2010, Dudley 2018). Additionally, BRCA2 c.1929delG has been reported to be a pathogenic founder variant in Northwest England (Evans 2004, Higgs 2015). We therefore consider this variant to be pathogenic.
Counsyl RCV000031350 SCV000220899 pathogenic Breast-ovarian cancer, familial 2 2014-11-20 criteria provided, single submitter literature only
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000195352 SCV000271322 pathogenic Hereditary breast and ovarian cancer syndrome 2016-02-08 criteria provided, single submitter clinical testing The p.Arg645fs variant in BRCA2 has been reported in >50 individuals with BRCA2- associated cancers (Evans, 2004, Janavicius 2010, Breast Cancer Information Core (BIC) database). This variant was absent from large population studies, though the ability of these studies to accurately detect indels may be limited. This va riant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 645 and leads to a premature termination codon 15 amino acids downstream. This alteration is then predicted to lead to a truncate d or absent protein. Heterozygous loss of function of the BRCA2 gene is an estab lished disease mechanism for hereditary breast and ovarian cancer (HBOC). In sum mary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein.
Color RCV000131475 SCV000292129 pathogenic Hereditary cancer-predisposing syndrome 2016-08-16 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000043926 SCV000296653 pathogenic not provided 2015-10-24 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031350 SCV000326637 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000195352 SCV000591783 pathogenic Hereditary breast and ovarian cancer syndrome 2015-11-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000195352 SCV000694578 pathogenic Hereditary breast and ovarian cancer syndrome 2016-04-26 criteria provided, single submitter clinical testing Variant summary: The c.1929delG (p.Arg645Glufs) variant in BRCA2 gene is a frame shift predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant has been reported in multiple affected individuals and was shown to segregate with the disease in a multiple families family. The variant is absent from the large control population dataset of ExAC. Lastly, multiple reputable databases/diagnostic centers have classified the variant of interest as Pathogenic. Taken together, the variant was classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000043926 SCV000862704 pathogenic not provided 2018-08-02 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031350 SCV000053955 pathogenic Breast-ovarian cancer, familial 2 2012-02-22 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031350 SCV000145979 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000195352 SCV000587619 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
GenomeConnect, ClinGen RCV000043926 SCV000607354 not provided not provided no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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