ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5073dupA (p.Trp1692Metfs) (rs80359479)

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Total submissions: 20
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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) RCV000031524 SCV000282397 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 RCV000044550 SCV000072563 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp1692Metfs*3) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs766647221, ExAC 0.002%). This variant has been reported in individuals affected with breast and/or ovarian cancer, pancreatic cancer, and Fanconi anemia (PMID: 11179017, 16683254, 10923033, 22144684, 26787237, 25479140, 14559878). This variant is also known as 5301insA, 5302insA, and c.5066_5067insA in the literature. ClinVar contains an entry for this variant (Variation ID: 37943). 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 RCV000130743 SCV000185634 pathogenic Hereditary cancer-predisposing syndrome 2017-11-14 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)
GeneDx RCV000160294 SCV000210759 pathogenic not provided 2018-11-27 criteria provided, single submitter clinical testing This duplication of one nucleotide is denoted BRCA2 c.5073dupA at the cDNA level and p.Trp1692MetfsX3 (W1692MfsX3) at the protein level. The normal sequence, with the base that is duplicated in brackets, is CAAAAAA[dupA]TGGC. The duplication causes a frameshift, which changes a Tryptophan to a Methionine at codon 1692, 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. BRCA2 c.5073dupA, previously reported as 5301dupA or 5301insA using alternate nomenclature, has been reported in multiple breast and ovarian cancer families and has been reported to occur de novo in at least one case (Sutter 2004, Marshall 2009, Laarabi 2011, Elalaoui 2013, de Juan 2015). We consider this variant to be pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768597 SCV000219346 pathogenic Breast and/or ovarian cancer 2017-07-25 criteria provided, single submitter clinical testing
Counsyl RCV000031524 SCV000220690 pathogenic Breast-ovarian cancer, familial 2 2014-09-11 criteria provided, single submitter literature only
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000044550 SCV000271329 pathogenic Hereditary breast and ovarian cancer syndrome 2016-02-08 criteria provided, single submitter clinical testing The p.Trp1692fs variant in BRCA2 has been identified in >30 individuals of vario us ethnicities with Fanconi anemia or BRCA2-related cancers (Risch 2001, Offit 2 003, Van Der Hout 2006, Laarabi 2011, Breast Cancer Information Core database). It has also been identified in 1/65240 European chromosomes by the Exome Aggreg ation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs80359480). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 1692 and leads to a premature termination codon 3 amino acids downst ream. 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 mech anism in HBOC. In addition, this variant was classified as Pathogenic on April 2 2, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282397.1). In summary, this variant meets our criteria to be classified as pathogenic for HBO C in an autosomal dominant manner.
Color RCV000130743 SCV000292169 pathogenic Hereditary cancer-predisposing syndrome 2015-04-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160294 SCV000296735 pathogenic not provided 2015-02-04 criteria provided, single submitter clinical testing
GeneKor MSA RCV000160294 SCV000296824 pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031524 SCV000327126 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000044550 SCV000591938 pathogenic Hereditary breast and ovarian cancer syndrome 2014-10-23 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000031524 SCV000593745 pathogenic Breast-ovarian cancer, familial 2 2016-11-30 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000031524 SCV000605702 pathogenic Breast-ovarian cancer, familial 2 2017-01-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000044550 SCV000694826 pathogenic Hereditary breast and ovarian cancer syndrome 2017-08-10 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5073dupA (p.Trp1692Metfs) 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.5130_5133delTGTA [p.Tyr1710fs). MutationTaster predicts a damaging outcome for this variant. This variant is absent in 119116 control chromosomes (ExAC). The variant has been found in numerous patients/families with breast and/or ovarian cancer, including a confirmed de novo breast cancer case (Marshall_Clin Genet_2009). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000031524 SCV000840551 pathogenic Breast-ovarian cancer, familial 2 2018-07-12 criteria provided, single submitter research
Sharing Clinical Reports Project (SCRP) RCV000031524 SCV000054129 pathogenic Breast-ovarian cancer, familial 2 2012-10-03 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031524 SCV000146530 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 RCV000044550 SCV000587741 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Gharavi Laboratory,Columbia University RCV000160294 SCV000809446 pathogenic not provided 2018-09-16 no assertion criteria provided research

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