ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5681dupA (p.Tyr1894Terfs) (rs80359527)

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Total submissions: 16
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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) RCV000031569 SCV000282411 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 RCV000044718 SCV000072731 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr1894*) 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 observed in individual(s) with breast and/or ovarian cancer (PMID: 11241844, 16683254, 23697973). This variant is also known as 5909insA in the literature. ClinVar contains an entry for this variant (Variation ID: 37988). 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 RCV000129296 SCV000184057 pathogenic Hereditary cancer-predisposing syndrome 2018-10-30 criteria provided, single submitter clinical testing ​<span style="background-color:initial">The c.5681dupA pathogenic mutation (also known as p.Y1894*), located in coding exon 10 of the BRCA2 gene, results from a duplication of A at position 5681. This changes the amino acid from a tyrosine to a stop codon within coding exon 10. This pathogenic mutation has been previously reported in Asian, European, and South American breast/ovarian cohorts (van der Hout AH et al. Hum. Mutat. 2006 Jul;27(7):654-66​; <span style="background-color:initial">Li WF et al. Breast Cancer Res. Treat. 2008 Jul;110(1):99-109; Solano AR et al. Springerplus. 2012 Sep;1:20; Castro M et al. Case Rep. Oncol. 2016 Jul;9(2):387-394; Sun J et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119; Wen WX et al. J. Med. Genet. 2018 Feb;55(2):97-103; Palmero EI et al. Sci. Rep. 2018 Jun;8(1):9188<span style="background-color:initial">). Of note, this alteration is also designated as 5909insA in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000031569 SCV000296655 pathogenic Breast-ovarian cancer, familial 2 2015-11-17 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031569 SCV000327262 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031569 SCV000488449 pathogenic Breast-ovarian cancer, familial 2 2016-03-31 criteria provided, single submitter clinical testing
GeneDx RCV000482761 SCV000564787 pathogenic not provided 2018-12-27 criteria provided, single submitter clinical testing This duplication of one nucleotide is denoted BRCA2 c.5681dupA at the cDNA level and p.Tyr1894Ter (Y1894X) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TGTT[dupA]CGAG. The duplication creates a nonsense variant, which changes a Tyrosine to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, previously reported as BRCA2 5909insA, has been observed in association with hereditary breast and ovarian cancer (Verhoog 1999, Tai 2007, Cao 2016). This variant is considered pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000044718 SCV000605821 pathogenic Hereditary breast and ovarian cancer syndrome 2017-06-12 criteria provided, single submitter clinical testing The p.Tyr1894X variant in BRCA2 has been reported in at least 8 individuals here ditary breast and or ovarian cancer (HBOC; Edwards 2001, Li 2008, Solano 2012, B reast Cancer Information Core (BIC) database) and one individual with unknown cl inical status with a possible history of familial breast and/or ovarian cancer w ho underwent genetic screening for BRCA1 and BRCA2 (van der Hout 2006). It was a lso identified in 1/17242 of East Asian chromosomes by the Genome Aggregation Da tabase (gnomAD; http://gnomad.broadinstitude.org; dbSNP rs80359527); however, th is frequency is low enough to be consistent with the frequency of HBOC in the ge neral population. This nonsense variant is a result of a duplication of one base pair at position 5681, which creates a premature termination codon at amino aci d position 1894. This alteration is then predicted to lead to a truncated or abs ent protein. Heterozygous loss of function of the BRCA2 gene is an established d isease mechanism in hereditary breast and ovarian cancer. Moreover, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA e xpert panel (SCV000282411.1). In summary, this variant meets criteria to be clas sified as pathogenic for hereditary breast and ovarian cancer in an autosomal do minant manner based upon predicted impact on the protein, presence in multiple a ffected individuals and low frequency in controls.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000482761 SCV000887856 pathogenic not provided 2020-01-03 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
Color Health, Inc RCV000129296 SCV000911073 pathogenic Hereditary cancer-predisposing syndrome 2020-12-11 criteria provided, single submitter clinical testing This variant inserts an adenine nucleotide into exon 11 creating a premature stop signal. To our knowledge, functional studies have not been reported for this variant. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 16683254, 17851763, 27153395, 27463008, 28294317, 28724667, 28993434, 29907814). This variant has been identified in 1/250446 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044718 SCV000916895 pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-03 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5681dupA (p.Tyr1894X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250446 control chromosomes. c.5681dupA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples Hamann_2002, Tai_2007, Solano_2012, Rebbeck_2018). 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. Ten other ClinVar submitters (evaluation after 2014) have cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000482761 SCV001334480 pathogenic not provided 2020-02-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV001262533 SCV001440450 pathogenic Familial cancer of breast 2019-01-01 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031569 SCV000054174 pathogenic Breast-ovarian cancer, familial 2 2011-11-29 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031569 SCV000146665 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 RCV000044718 SCV000587790 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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