ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.5350_5351del (p.Asn1784fs)

dbSNP: rs80359507
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Total submissions: 36
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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) RCV000031540 SCV000282406 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000044639 SCV000072652 pathogenic Hereditary breast ovarian cancer syndrome 2024-01-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn1784Hisfs*2) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs769126974, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10923033, 21324516, 22006311, 22144684, 23633455). This variant is also known as 5573delAA and 5578delAA. ClinVar contains an entry for this variant (Variation ID: 37959). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000074537 SCV000108622 pathogenic not provided 2020-06-24 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5578delAA; This variant is associated with the following publications: (PMID: 23569316, 22006311, 23633455, 24504028, 17148771, 8988179, 9150172, 21233401, 11597388, 21324516, 26681312, 17688236, 16683254, 23725378, 21305653, 28008555, 27836010, 24094589, 29371908, 29084914, 28687971, 30720243, 30322717, 26689913, 31447099, 32853339, 32719484, 32338768, 30787465, 33087929, 31360904)
Ambry Genetics RCV000131110 SCV000186040 pathogenic Hereditary cancer-predisposing syndrome 2023-09-15 criteria provided, single submitter clinical testing The c.5350_5351delAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides between positions 5350 and 5351 causing a translational frameshift with a predicted alternate stop codon (p.N1784Hfs*2). This mutation is located in the ovarian cancer cluster region (OCCR) of BRCA2 and has been detected in patients from multiple ovarian cancer series to date (Gayther SA et al. Nat. Genet. 1997 Jan;15:103-5; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; George J et al. Clin. Cancer Res. 2013 Jul;19:3474-84). This mutation has also been detected in a prostate cancer patient (Castro E et al. J. Clin. Oncol. 2013 May;31:1748-57) and a male breast cancer patient (Pritzlaff M et al. Breast Cancer Res. Treat. 2017 02;161(3):575-586). Of note, this alteration is also designated as 5573delAA and 5578delAA 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.
Michigan Medical Genetics Laboratories, University of Michigan RCV000031540 SCV000195990 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2014-11-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000074537 SCV000296699 pathogenic not provided 2023-07-19 criteria provided, single submitter clinical testing The BRCA2 c.5350_5351del (p.Asn1784Hisfs*2) variant (also known as 5578delAA and 5573delAA) alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with ovarian cancer (PMID: 21324516 (2011), 22006311 (2011), 23633455 (2013), 24504028 (2014)), breast cancer (PMID: 28008555 (2017), 31360904 (2019)), prostate cancer (PMID: 28687971 (2018), 32338768 (2020)), and pancreatic cancer (PMID: 29922827 (2018)). The frequency of this variant in the general population, 0.000032 (1/31198 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031540 SCV000327201 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2015-10-02 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000044639 SCV000605783 pathogenic Hereditary breast ovarian cancer syndrome 2019-04-24 criteria provided, single submitter clinical testing The p.Asn1784HisfsX2 variant in BRCA2 has been identified in >30 individuals with BRCA2-associated cancers (Gayther 1997, Walsh 2011, Zhang 2011, George 2013, Cunningham 2014, Breast Cancer Information Core (BIC) database, Sharing Clinical Reports Project). This variant has been identified in 1/15316 of European chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org); however, 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 1784 and leads to a premature termination codon 2 amino acids downstream. 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 mechanism in individuals with hereditary breast and ovarian cancer (HBOC). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein. ACMG/AMP criteria applied: PVS1, PS4, PM2.
Counsyl RCV000031540 SCV000677682 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2015-07-08 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000131110 SCV000683699 pathogenic Hereditary cancer-predisposing syndrome 2023-02-20 criteria provided, single submitter clinical testing This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 5573delAA, 5578delAA, and c.5351_5352delAA in the literature. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least eight individuals affected with ovarian cancer (PMID: 21324516, 22006311, 23633455, 24728189, 29084914), peritoneal cancer (PMID: 22006311) and individuals affected triple-negative or male breast cancer (PMID: 21233401, 28008555) and at least two families affected with both breast and ovarian cancer (PMID: 8988179, 9150172). This variant also has been observed in individuals affected with pancreatic and prostate cancer (PMID: 23569316, 28687971). This variant has been identified in 1/31198 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 RCV000044639 SCV000694862 pathogenic Hereditary breast ovarian cancer syndrome 2016-05-02 criteria provided, single submitter clinical testing Variant summary: The c.5350_5351delAA variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.5386_5387delGA/p.Asp1796fs). One in-silico tool predicts damaging outcome for this variant. This variant is absent in 122212 control chromosomes. In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000031540 SCV000744468 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2015-09-21 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000031540 SCV000839933 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2018-02-25 criteria provided, single submitter clinical testing This c.5350_5351delAA (p.Asn1784Hisfs*2) frameshift variant in the BRCA2 gene is predicted to introduce a premature translation termination codon and has been reported in multiple unrelated individuals with breast, ovarian, prostate, fallopian, and/or peritoneal cancer (PMID: 8988179, 21324516, 22006311, 23569316, 23633455, 24504028). The c.5350_5351delAA (p.Asn1784Hisfs*2) variant in the BRCA2 gene is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000074537 SCV000883477 pathogenic not provided 2020-08-27 criteria provided, single submitter clinical testing The BRCA2 c.5350_5351delAA; p.Asn1784fs variant (rs80359507) has been identified in multiple individuals diagnosed with ovarian, fallopian tube or peritoneal cancer (Gayther 1997, Walsh 2011, Zhang 2011, Cunningham 2014). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37959) and observed in only 1/30754 alleles in the Genome Aggregation Database. This variant causes a frameshift by deleting 2 nucleotides, so is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on the above information, this variant is considered pathogenic. References: Cunningham J et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014. 4:4026. Gayther S et al. Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet. 1997. 15(1):103-5. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing.Proc Natl Acad Sci U S A. 2011. 108(44):18032-7. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer.Gynecol Oncol. 2011. 121(2):353-7.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000031540 SCV000993555 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2018-09-07 criteria provided, single submitter research
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000031540 SCV001251945 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2020-05-03 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000074537 SCV001447454 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000074537 SCV002024787 pathogenic not provided 2024-01-04 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798045 SCV002043168 pathogenic Breast and/or ovarian cancer 2022-01-28 criteria provided, single submitter clinical testing
Daryl Scott Lab, Baylor College of Medicine RCV002243676 SCV002515298 pathogenic Fanconi anemia complementation group D1 2022-02-01 criteria provided, single submitter clinical testing
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health RCV000044639 SCV002522182 pathogenic Hereditary breast ovarian cancer syndrome 2021-08-06 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000131110 SCV002536129 pathogenic Hereditary cancer-predisposing syndrome 2021-11-17 criteria provided, single submitter curation
MGZ Medical Genetics Center RCV000031540 SCV002581390 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2022-02-23 criteria provided, single submitter clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000031540 SCV003843087 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2023-03-08 criteria provided, single submitter clinical testing The BRCA2 c.5350_5351del (p.Asn1784HisfsTer2) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay. This variant has been reported in several individuals with hereditary breast and ovarian cancer (HBOC)-related cancers, including ovarian cancer (PMID: 30322717, 23633455, 21324516, 22006311), breast cancer (PMID: 31360904), pancreatic cancer (PMID: 29922827), and prostate cancer (PMID: 32338768). It has a maximum subpopulation frequency of 0.0065% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant is also known as 5573delAA and c.5578delAA in the literature. In summary, this variant meets criteria to be classified as pathogenic.
Baylor Genetics RCV000031540 SCV004041535 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2023-08-17 criteria provided, single submitter clinical testing
Baylor Genetics RCV003473185 SCV004211933 pathogenic Familial cancer of breast 2023-09-22 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV001535625 SCV004718772 pathogenic BRCA2-related disorder 2024-02-01 criteria provided, single submitter clinical testing The BRCA2 c.5350_5351delAA variant is predicted to result in a frameshift and premature protein termination (p.Asn1784Hisfs*2). This variant (also described as 5573del and 5578del) has been reported as pathogenic in patients with breast and ovarian cancer (Gayther et al. 1997. PubMed ID: 8988179; Walsh et al. 2011. PubMed ID: 22006311; Cunningham et al. 2014. PubMed ID: 24504028). This variant is reported in 0.0065% of alleles in individuals of non-Finnish European descent in gnomAD (https://gnomad.broadinstitute.org/variant/13-32913836-CAA-C) and it has been reported as pathogenic in ClinVar by multiple clinical labs as well as the ENIGMA expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/37959/). Based on the available evidence, we consider the BRCA2 c.5350_5351del variant to be pathogenic.
All of Us Research Program, National Institutes of Health RCV000031540 SCV004846562 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2024-01-05 criteria provided, single submitter clinical testing This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 5573delAA, 5578delAA, and c.5351_5352delAA in the literature. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least eight individuals affected with ovarian cancer (PMID: 21324516, 22006311, 23633455, 24728189, 29084914), peritoneal cancer (PMID: 22006311) and individuals affected triple-negative or male breast cancer (PMID: 21233401, 28008555) and at least two families affected with both breast and ovarian cancer (PMID: 8988179, 9150172). This variant also has been observed in individuals affected with pancreatic and prostate cancer (PMID: 23569316, 28687971). This variant has been identified in 1/31198 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.
Sharing Clinical Reports Project (SCRP) RCV000031540 SCV000054145 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2012-07-17 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031540 SCV000146602 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto RCV000044639 SCV000587763 pathogenic Hereditary breast ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001353434 SCV000591962 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Asn1784Hisfsx2 variant was identified in 6 of 9066 proband chromosomes (frequency: 0.0007) from individuals or families with breast, ovarian or prostate cancer (Gayther 1997 PMID:8988179, George 2013 PMID:23633455, Gonzalez-Angulo 2011 PMID:21233401, Walsh 2011 PMID:22006311, Zhang 2011 PMID:21324516, Castro 2013 PMID:23569316). The variant was also identified in the following databases: dbSNP (ID: rs80359507) as “With Pathogenic allele”, ClinVar (reported 14x as pathogenic by ENIGMA, Quest Diagnostics, CIMBA, Invitae, GeneDx, Ambry, University of Michigan, Counsyl, Color Genomics, SCRO, BIC, COGAR), Clinvitae (reported 5x as pathogenic by Invitae , ClinVar and kConFab), LOVD 3.0 (reported 10x as "affects function"), UMD-LSDB (23 records, as 5-causal), BIC Database (reported 33x, as class 5 ), ARUP Laboratories (as definitely pathogenic). The variant was not identified in Cosmic, MutDB and Zhejiang Colon Cancer Databases. The variant was also identified by our laboratory in 1 individual with breast cancer. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.5350_5351delAA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1784 and leads to a premature stop codon 2 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000031540 SCV000733267 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000074537 SCV000778684 pathogenic not provided 2017-12-12 no assertion criteria provided clinical testing
GenomeConnect - Invitae Patient Insights Network RCV001535625 SCV001749651 not provided BRCA2-related disorder no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 09-18-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000074537 SCV002037534 pathogenic not provided no assertion criteria provided clinical testing

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