ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6405_6409del (p.Asn2135fs) (rs80359584)

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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
3DMed Clinical Laboratory Inc RCV000677858 SCV000804019 pathogenic Cancer of the pancreas 2017-11-20 criteria provided, single submitter clinical testing
Academic Department of Medical Genetics, University of Cambridge RCV000162930 SCV000992214 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research 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.
Ambry Genetics RCV000162930 SCV000213417 pathogenic Hereditary cancer-predisposing syndrome 2018-03-14 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)
Baylor Genetics RCV000456954 SCV000541014 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031625 SCV000146844 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000162930 SCV000292150 pathogenic Hereditary cancer-predisposing syndrome 2016-04-11 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031625 SCV000327416 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031625 SCV000785311 pathogenic Breast-ovarian cancer, familial 2 2017-07-05 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031625 SCV000744491 pathogenic Breast-ovarian cancer, familial 2 2017-05-31 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000044934 SCV000592048 pathogenic Hereditary breast and ovarian cancer syndrome 2012-11-05 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000031625 SCV000733282 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Division Human Genetics,Medical University Innsbruck RCV000031625 SCV000212026 pathogenic Breast-ovarian cancer, familial 2 2015-02-11 no assertion criteria provided clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031625 SCV000282424 pathogenic Breast-ovarian cancer, familial 2 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000160301 SCV000210779 pathogenic not provided 2018-11-19 criteria provided, single submitter clinical testing This deletion of five nucleotides is denoted BRCA2 c.6405_6409delCTTAA at the cDNA level and p.Asn2135LysfsX3 (N2135KfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ATAA[delCTTAA]ATGT. The deletion causes a frameshift, which changes an Asparagine to a Lysine at codon 2135, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Also reported as BRCA2 6633del5 or 6402_6406delTAACT using alternate nomenclature, this variant has been observed in multiple families with breast and/or ovarian cancer and in men with early-onset prostate cancer (Wagner 1999, Gomes 2007, Machackova 2008, Kote-Jarai 2011, Zhang 2011, Cybulski 2014, de Juan 2015, Alemar 2016, Sakamoto 2016). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000044934 SCV000694970 pathogenic Hereditary breast and ovarian cancer syndrome 2017-05-15 criteria provided, single submitter clinical testing Variant summary: The c.6405_6409delCTTAA (p.Asn2135Lysfs) variant in BRCA2 gene is a frameshift change that results in the loss of the ~38% of the length of the protein (1282 aa). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The variant is present in the large control population dataset of ExAC at a low frequency 8.471e-06 (1/118050 chrs tested). This frequency does not exceed the maximal expected frequency of a pathogenic allele (0.00075) in this gene. The variant of interest has been reported in numerous affected individual in the literature and cited as Pathogenic by multiple reputable database/diagnostic centers. Taking together, the variant was classified as Pathogenic.
Invitae RCV000044934 SCV000072947 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn2135Lysfs*3) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80359584, ExAC 0.009%). This variant has been observed in individuals with breast, ovarian, and prostate cancer (PMID: 25802882, 21324516, 8988179, 21952622, 26026974, 17063270, 11179017). This variant is also known as c.6402_6406delTAACT, 6630del5, and 6633del5 in the literature. ClinVar contains an entry for this variant (Variation ID: 38043). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000044934 SCV000605796 pathogenic Hereditary breast and ovarian cancer syndrome 2016-10-20 criteria provided, single submitter clinical testing The p.Asn2135fs variant in BRCA2 has been reported in at least 12 individuals wi th BRCA2-associated cancers (Gayther 1997, Wagner 1999, Risch 2001, Gomes 2007, Machackova 2008, Kote-Jarai 2011, Zhang 2011, de Juan 2015, Hirotsu 2015, Breast Cancer Information Core database, www.research.nhgri.nih.gov/bic/). This varian t has also been identified in 1/11488 of Latino chromosomes by the Exome Aggrega tion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs80359585). This f requency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted t o cause a frameshift, which alters the protein?s amino acid sequence beginning a t position 2135 and leads to a premature termination codon 3 amino acids downstr eam. 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 mecha nism in HBOC. In addition, this variant was classified as Pathogenic on April 22 , 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282424.1). In summary, 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.
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240801 SCV000265903 pathogenic Neoplasm of the breast 2015-11-01 criteria provided, single submitter research
Mendelics RCV000044934 SCV000838838 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160301 SCV000296661 pathogenic not provided 2015-05-30 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044934 SCV000587843 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031625 SCV000054232 pathogenic Breast-ovarian cancer, familial 2 2012-07-02 no assertion criteria provided clinical testing

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