ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3264dupT (p.Gln1089Serfs) (rs80359380)

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Total submissions: 18
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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) RCV000031411 SCV000300607 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 RCV000203627 SCV000072176 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln1089Serfs*10) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 12845657, 20033483, 22426013, 24123850, 25136594), as well as in an individual affected with Fanconi anemia (PMID: 23613520). This variant is a common cause of breast and ovarian cancer among Spanish and American individuals of Latin American descent (PMID: 16030099, 19941167). This variant is also known as 3492insT and 3492_3493insT in the literature. ClinVar contains an entry for this variant (Variation ID: 37830). 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 RCV000131493 SCV000186481 pathogenic Hereditary cancer-predisposing syndrome 2019-03-18 criteria provided, single submitter clinical testing The c.3264dupT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of T at nucleotide position 3264, causing a translational frameshift with a predicted alternate stop codon (p.Q1089Sfs*10). This alteration has been reported as a pathogenic mutation in numerous Spanish and Mexican breast and/or ovarian cancer kindreds (Llort G et al. Hum. Mutat. 2002 Mar;19:307; Weitzel JN et al. J. Clin. Oncol. 2013 Jan;31:210-6; Susswein LR et al. Genet Med. 2016 Aug;18(8):823-832; Gabaldo Barrios X et al. Fam. Cancer. 2017 Oct;16(4):477-489). This alteration has also been observed in Fanconi anemia patients (Myers K et al. Pediatr. Blood Cancer. 2012 Mar;58:462-5; Chandrasekharappa SC et al. Blood 2013 May;121:e138-48) and in a patient with pancreatic cancer (Lowery MA et al. J. Natl. Cancer Inst. 2018 Oct;110(10):1067-1074). Of note, this alteration is also designated as 3492insT 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.
GeneDx RCV000044163 SCV000210736 pathogenic not provided 2018-09-18 criteria provided, single submitter clinical testing This duplication of one nucleotide in BRCA2 is denoted c.3264dupT at the cDNA level and p.Gln1089SerfsX10 (Q1089SfsX10) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ACCCC[dupT]CAGA. The duplication causes a frameshift, which changes a Glutamine to a Serine at codon 1089, and creates a premature stop codon at position 10 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.3264dupT, also published as BRCA2 3492insT and BRCA2 3264_3265insT, has been observed in many breast/ovarian cancer families, the majority of which are of Spanish descent (Diez 2003, Esteban Carde?osa 2010, Weitzel 2013, de Juan Jim?nez 2013, Nahleh 2015, Gabald? Barrios 2017). Additionally, this variant has been observed in the compound heterozygous state in a patient with Fanconi Anemia (Myers 2012). Based on currently available evidence, we consider this variant to be pathogenic.
Counsyl RCV000031411 SCV000220688 likely pathogenic Breast-ovarian cancer, familial 2 2014-09-11 criteria provided, single submitter literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000044163 SCV000296687 pathogenic not provided 2019-08-30 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031411 SCV000326841 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Baylor Genetics RCV000459431 SCV000541003 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131493 SCV000683540 pathogenic Hereditary cancer-predisposing syndrome 2020-10-20 criteria provided, single submitter clinical testing This variant inserts 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 3492insT and 3492_3493insT in the literature. This variant is expected to result in an absent or non-functional protein product. This variant is a common cause of breast and/or ovarian cancer in the Hispanic population (PMID: 16030099, 19941167, 23233716). This variant has been identified in 6/232856 chromosomes (6/30610 Latino 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 RCV000203627 SCV000694685 pathogenic Hereditary breast and ovarian cancer syndrome 2016-08-03 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.3264dupT (p.Gln1089Serfs) 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. The variant of interest was not found in controls (ExAC, 1000 Gs or ESP) and has been reported in multiple affected individuals by publications. Multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Pathogenic.
PreventionGenetics,PreventionGenetics RCV000044163 SCV000805689 pathogenic not provided 2018-01-17 criteria provided, single submitter clinical testing
Mendelics RCV000203627 SCV000838786 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Division of Medical Genetics, University of Washington RCV000031411 SCV001434321 pathogenic Breast-ovarian cancer, familial 2 2020-03-07 criteria provided, single submitter clinical testing This variant inserts a single nucleotide causing a frameshift at position 1089 which leads to a premature stop codon. This variant is predicted to result in a loss of protein function, which is a well-established mechanism of disease for the BRCA2 gene (Borg 2010). This variant has been observed in many families with breast and/or ovarian cancer, especially families with Spanish ancestry (Diez 2010, de Sanjose 2003, Esteban Cardenosa 2010, Weitzel 2005), and in an individual with Fanconi anemia (Chandrasekharappa 2013). Based on this information, we consider this variant to be pathogenic. PS4-moderate; PVS1
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285484 SCV001471919 pathogenic none provided 2019-08-01 criteria provided, single submitter clinical testing The BRCA2 c.3264dupT; p.Gln1089fs variant (rs80359380), also known as 3492insT, is reported in the literature in multiple individuals with a personal or family history of breast and/or ovarian cancer (de Juan 2015, de la Hoya 2002, Fernandez-Lopez 2019, Llort 2002, Plamero 2018). This variant has also been observed in an individual with Fanconi anemia in trans to a second pathogenic BRCA2 variant (Chandrasekharappa 2013). The c.3264dupT variant is found on only six chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Chandrasekharappa SC et al. Massively parallel sequencing, aCGH, and RNA-Seq technologies provide a comprehensive molecular diagnosis of Fanconi anemia. Blood. 2013 May 30;121(22):e138-48. de Juan I et al. BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study. Fam Cancer. 2015 Dec;14(4):505-13. de la Hoya M et al. Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: implications for genetic testing. Int J Cancer. 2002 Feb 1;97(4):466-71. Fernandez-Lopez JC et al. Population and breast cancer patients' analysis reveals the diversity of genomic variation of the BRCA genes in the Mexican population. Hum Genomics. 2019 Jan 10;13(1):3. Llort G et al. Low frequency of recurrent BRCA1 and BRCA2 mutations in Spain. Hum Mutat. 2002 Mar;19(3):307. Palmero EI et al. The germline mutational landscape of BRCA1 and BRCA2 in Brazil. Sci Rep. 2018 Jun 15;8(1):9188.
Sharing Clinical Reports Project (SCRP) RCV000031411 SCV000054016 pathogenic Breast-ovarian cancer, familial 2 2012-12-27 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031411 SCV000146201 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 RCV000203627 SCV000587668 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785218 SCV000923786 pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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