ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1813dupA (p.Ile605Asnfs) (rs80359306)

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Total submissions: 24
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Academic Department of Medical Genetics, University of Cambridge RCV000131453 SCV000992210 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 RCV000131453 SCV000186437 pathogenic Hereditary cancer-predisposing syndrome 2017-07-20 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)
Breast Cancer Information Core (BIC) (BRCA2) RCV000031343 SCV000145951 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768624 SCV000219309 pathogenic Breast and/or ovarian cancer 2017-10-11 criteria provided, single submitter clinical testing
Color RCV000131453 SCV000683453 pathogenic Hereditary cancer-predisposing syndrome 2015-04-05 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031343 SCV000326619 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031343 SCV000220297 pathogenic Breast-ovarian cancer, familial 2 2014-05-08 criteria provided, single submitter literature only
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000043897 SCV000591772 pathogenic Hereditary breast and ovarian cancer syndrome 2014-08-21 criteria provided, single submitter clinical testing
Division Human Genetics,Medical University Innsbruck RCV000031343 SCV000212013 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) RCV000031343 SCV000282363 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 RCV000160269 SCV000210718 pathogenic not provided 2018-10-30 criteria provided, single submitter clinical testing This duplication of one nucleotide in BRCA2 is denoted c.1813dupA at the cDNA level and p.Ile605AsnfsX11 (I605NfsX11) at the protein level. The normal sequence, with the base that is duplicated in brackets, is GAAAAAAA[dupA]TACC. The duplication causes a frameshift, which changes an Isoleucine to an Asparagine at codon 605, and creates a premature stop codon at position 11 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. BRCA2 c.1813dupA, previously reported as BRCA2 2041dupA or 2041insA using alternate nomenclature, has been reported in association with hereditary breast and ovarian cancer (Frank 1998, Foretova 2004, Becker 2012, Blay 2013), and in individuals with male breast cancer and/or prostate cancer (Tai 2007, Kote-Jarai 2011, Pritzlaff 2017, Ibrahim 2018). We consider this variant to be pathogenic.
GeneKor MSA RCV000043897 SCV000693558 pathogenic Hereditary breast and ovarian cancer syndrome 2017-11-01 criteria provided, single submitter clinical testing
Genologica Medica RCV000031343 SCV000577948 pathogenic Breast-ovarian cancer, familial 2 2017-01-01 criteria provided, single submitter clinical testing
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000031343 SCV000746277 pathogenic Breast-ovarian cancer, familial 2 2017-12-03 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000031343 SCV000839914 pathogenic Breast-ovarian cancer, familial 2 2017-05-25 criteria provided, single submitter clinical testing The c.1813dup (p.Ile605Asnfs*11) variant in the BRCA2 gene has been detected in multiple patients with breast and/or ovarian cancer [referred as 2034insA and 2041insA in PMID 9150150, 21324516, 22535016] and prostate cancer [PMID 21952622].This variant has been reported in four individuals from the ExAC database (http://exac.broadinstitute.org/variant/22-29091226-TA-T). This one bp duplication in exon 10 results in a frameshift and the creation of a premature stop codon. This variant is expected to result in a loss of function of the protein. It is thus classified as pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000043897 SCV000918819 pathogenic Hereditary breast and ovarian cancer syndrome 2017-10-20 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.1813dupA (p.Ile605AsnfsX11) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1842dupT/ p.Asn615X, c.1889delC/ p.Thr630fsX14, etc). One in silico tool predicts a damaging outcome for this variant. This variant was found in 8/227550 control chromosomes at a frequency of 0.0000352, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in numerous affected individuals/families and has been classified this variant as pathogenic by multiple clinical diagnostic laboratories/reputable databases. Functional study showed variant with diminished DNA double strand break repair capacity (Becker_2012). Taken together, this variant is classified as pathogenic.
Invitae RCV000043897 SCV000071910 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ile605Asnfs*11) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs768562561, ExAC 0.005%). This variant has been reported in individuals affected with breast, ovarian, and prostate cancer (PMID: 9150150, 22535016, 22729890, 21324516, 21952622). This variant is also known as 1813insA, 2041insA, and 2034insA in the literature. ClinVar contains an entry for this variant (Variation ID: 37762). 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 RCV000043897 SCV000605784 pathogenic Hereditary breast and ovarian cancer syndrome 2016-02-08 criteria provided, single submitter clinical testing The p.Ile605fs variant in BRCA2 has been reported in >75 individuals with BRCA2- associated cancers (Breast Cancer Information Core (BIC) database), and segregat ed with disease in 7 affected relatives from 1 family (Schubert 1997). This vari ant has also been identified in 3/63362 European chromosomes by the Exome Aggreg ation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs80359306); howev er, this frequency is low enough to be consistent with the frequency of heredita ry breast and ovarian cancer (HBOC) in the general population. The p.Ile605fs va riant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 605 and leads to a premature termination codon 11 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 HBOC. In summary, this variant meets our criteria t o be classified as pathogenic for HBOC in an autosomal dominant manner based upo n segregation studies, absence from controls, and predicted impact to protein.
Mendelics RCV000043897 SCV000838762 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000031343 SCV000195964 pathogenic Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
PreventionGenetics RCV000160269 SCV000805657 pathogenic not provided 2018-01-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160269 SCV000296732 pathogenic not provided 2015-02-12 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000043897 SCV000587614 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031343 SCV000053947 pathogenic Breast-ovarian cancer, familial 2 2013-10-11 no assertion criteria provided clinical testing

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