ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4936_4939del (p.Glu1646fs) (rs80359473)

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Total submissions: 19
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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) RCV000031516 SCV000300803 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000198074 SCV000072540 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.Glu1646Glnfs*23) 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 families affected with Fanconi anemia (PMID: 15070707), and hereditary breast and ovarian cancer (PMID: 23479189, 22923021, 26350514, 20960228). This variant is also known as c.4933_4936delAAAG and 5164del4 in the literature. ClinVar contains an entry for this variant (Variation ID: 37935). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000074531 SCV000108616 pathogenic not provided 2018-08-17 criteria provided, single submitter clinical testing This deletion of four nucleotides is denoted BRCA2 c.4936_4939delGAAA at the cDNA level and p.Glu1646GlnfsX23 (E1646QfsX23) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GAAAAA[delGAAA]CAGC. The deletion causes a frameshift, which changes a Glutamic Acid to a Glutamine at codon 1646, and creates a premature stop codon at position 23 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. This deletion, previously published as BRCA2 5164del4 using alternate nomenclature, has been reported in multiple breast/ovarian cancer families (Kaufman 2006, Stegel 2011, Novakovic 2012, de Juan Jimenez 2013, de Juan 2015, Hoberg-Vetti 2015, Bunnell 2016) and in the compound heterozygous state with a second pathogenic BRCA2 variant in two siblings with Fanconi anemia (Wagner 2004). We consider this variant to be pathogenic.
Ambry Genetics RCV000131071 SCV000186001 pathogenic Hereditary cancer-predisposing syndrome 2017-11-15 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)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000074531 SCV000296583 pathogenic not provided 2015-12-21 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031516 SCV000327106 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031516 SCV000487826 pathogenic Breast-ovarian cancer, familial 2 2015-11-23 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000031516 SCV000605698 pathogenic Breast-ovarian cancer, familial 2 2016-09-23 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000198074 SCV000605803 pathogenic Hereditary breast and ovarian cancer syndrome 2016-08-15 criteria provided, single submitter clinical testing The p.Glu1646fs variant in BRCA2 has been reported as heterozygous in >20 indivi duals with BRCA2-associated cancers and as compound heterozygous in 2 siblings w ith Fanconi anemia (H?berg-Vetti 2016, Jimenez 2013, Stegel 2011, Wagner 2004, B reast Cancer Information Core (BIC) database). It was absent from large populati on studies, though the ability of these studies to accurately detect indels may be limited. This variant is predicted to cause a frameshift, which alters the pr otein?s amino acid sequence beginning at position 1646 and leads to a premature termination codon 23 amino acids downstream. This alteration is then predicted t o lead to a truncated or absent protein. Heterozygous loss of function of the BR CA2 gene is an established disease mechanism in individuals with hereditary brea st and ovarian cancer (HBOC). In addition, this variant was classified as Pathog enic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar S CV000300803.2). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner .
Color RCV000131071 SCV000683662 pathogenic Hereditary cancer-predisposing syndrome 2015-04-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000198074 SCV000694813 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-03 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4936_4939delGAAA (p.Glu1646GlnfsX23) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 238878 control chromosomes (gnomAD). c.4936_4939delGAAA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Finkelman_2012, Infante_2006, Kaufman_2006, Krajc_2008, Borg_2010, Beristain_2010, de Juan Jimenez_2012, Novakovic_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Fourteen ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000074531 SCV000708871 pathogenic not provided 2017-06-02 criteria provided, single submitter clinical testing
GeneKor MSA RCV000198074 SCV000821711 pathogenic Hereditary breast and ovarian cancer syndrome 2018-08-01 criteria provided, single submitter clinical testing
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles RCV000735311 SCV000854464 pathogenic Migraine; Obesity; Short attention span; Muscle weakness; Headache; Nephrolithiasis; Striae distensae; Ectopic ossification; Asthma criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031516 SCV000054121 pathogenic Breast-ovarian cancer, familial 2 2012-12-17 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031516 SCV000146510 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 RCV000198074 SCV000587732 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000074531 SCV000778679 pathogenic not provided 2017-01-31 no assertion criteria provided clinical testing
True Health Diagnostics RCV000131071 SCV000787933 pathogenic Hereditary cancer-predisposing syndrome 2017-09-11 no assertion criteria provided clinical testing

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