ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5266dup (p.Gln1756fs)

dbSNP: rs80357906
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Total submissions: 80
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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) RCV000019246 SCV000282341 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000119097 SCV000076906 pathogenic Hereditary breast ovarian cancer syndrome 2024-01-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln1756Profs*74) in the BRCA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 108 amino acid(s) of the BRCA1 protein. This variant is present in population databases (rs397507247, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer. It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 9042909, 22185575, 22430266). This variant is also known as 5382insC and 5385insC. ClinVar contains an entry for this variant (Variation ID: 17677). This variant has been associated with a 67% to 89% risk of breast cancer by age 70, and a 33% to 42% risk of ovarian cancer by age 70 (PMID: 15994883, 22430266). This variant disrupts a region of the BRCA1 protein in which other variant(s) (Deletion (Exon 23)) have been determined to be pathogenic (PMID: 18431737, 24825132, 25428789; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131328 SCV000186302 pathogenic Hereditary cancer-predisposing syndrome 2022-05-24 criteria provided, single submitter clinical testing The c.5266dupC (p.Q1756Pfs*74) alteration, located in exon 19 (coding exon 18) of the BRCA1 gene, consists of a duplication of C at position 5266, causing a translational frameshift with a predicted alternate stop codon after amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration is one of three well-characterized Ashkenazi Jewish founder mutations, with an overall carrier frequency of nearly 0.5% in this population, but has also been shown to occur at high frequency in many other European populations (Hartge, 1999; Hamel, 2011; Kluz, 2018). Cumulative female breast cancer and ovarian cancer risks (by age 70) associated with this specific mutation have been estimated in the literature at 67% (range: 36-83%) and 33% (range: 8-50%), respectively (Antoniou, 2005). Of note, this mutation is also designated as 5382insC and 5385insC in the published literature. Based on the available evidence, this alteration is classified as pathogenic.
Michigan Medical Genetics Laboratories, University of Michigan RCV000019246 SCV000195938 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2014-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000258962 SCV000209886 pathogenic not provided 2020-02-12 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5382insC or 5385insC; This variant is associated with the following publications: (PMID: 25859162, 25849179, 27160020, 26843898, 26852130, 26833046, 27025497, 27062684, 26681312, 29790872, 26440929, 30067863, 31336956, 32854451, 24372583, 21119707, 26656232, 26083025, 25476495, 24528374, 25195694, 22032251, 7894492, 16168118, 27223485, 26779294, 27433846, 26666763, 26718727, 29478780, 27425403, 22009639, 20569256, 21503673, 23232912, 20345474, 22430266, 29335925, 28285342, 22535016, 29339979, 23954390, 29433453, 29335924, 29492181, 21834074, 24737347, 19359128, 27914478, 28324225, 22666503, 27989354, 29907814, 20730485, 28091860, 28503720, 26556299, 10464624, 28423363, 20507347, 22006311, 25980754, 21324516, 29310832, 30333958, 30159786, 29161300, 30606148, 30152102, 28049106, 28111427, 30186769, 29961768, 30322717, 31090900, 31159747, 30113427, 23199084, 8841191, 30676620, 30489631, 31454914, 12771565, 31528241, 27741520, 29625052, 26689913, 32058061, 31447099, 32039725)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000119097 SCV000219263 pathogenic Hereditary breast ovarian cancer syndrome 2017-02-02 criteria provided, single submitter clinical testing
Counsyl RCV000019246 SCV000220482 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2014-07-07 criteria provided, single submitter literature only
Eurofins Ntd Llc (ga) RCV000258962 SCV000226938 pathogenic not provided 2014-11-07 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000119097 SCV000271320 pathogenic Hereditary breast ovarian cancer syndrome 2022-11-23 criteria provided, single submitter clinical testing The p.Gln1756ProfsX74 variant in BRCA1 (also referred to as p.Gln1777fs) is a founder variant in the Ashkenazi Jewish population and has been reported in >1000 individuals with BRCA1-associated cancers (Abeliovich 1997 PMID: 9042909, Elwad 2011 PMID: 22185575, Breast Cancer Information Core (BIC) database). This variant has also been identified in 0.2% (24/103702) Ashkenazi Jewish and 0.02% (25/129200) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1756 and leads to a premature termination codon 74 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). Furthermore, the p.Gln1756ProfsX74 variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar ID 17677). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4, PVS1.
Color Diagnostics, LLC DBA Color Health RCV000131328 SCV000292125 pathogenic Hereditary cancer-predisposing syndrome 2023-03-20 criteria provided, single submitter clinical testing This variant (also known as 5382insC and 5385insC) inserts 1 nucleotide in exon 19 of the BRCA1 gene, causing a frameshift and a premature translational stop signal in the last exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a truncated protein that lacks the C-terminal BRCT domain. Experimental studies have shown that variant impacts BRCA1 function in homology-directed repair and subcellular localization assays (PMID: 14729053, 23867111). This variant is a well-known founder mutation in the Ashkenazi Jewish population and occurs at 0.13-0.28% minor allele frequency (PMID: 8841191, 9145676, 11466700, 30152102). This variant has been reported in numerous individuals affected with breast and/or ovarian cancer (PMID: 7545954, 7894492, 8531967, 9042909, 9150153, 17922257, 18334730, 21643751, 22430266, 25418591, 29335925, 30480775, 30606148, 30975216). This variant is the most globally frequent, pathogenic BRCA1 variant and has been reported in diverse populations in Africa, America, Asia and Europe (PMID: 24312913). The risk of female breast cancer among carriers of this mutation is 67-89% by age 70, and the risk of ovarian cancer is 22-42% by age 70 (PMID: 9145676, 15994883, 22430266). A breast cancer case-control meta-analysis has reported this variant in 97/60369 cases and 11/53450 controls with an estimated OR of 7.808 (95%CI 4.185 to 14.567) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000440). This variant has been identified in 51/282892 chromosomes (24/10370 Ashkenazi Jewish chromosomes and 25/129200 Non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000258962 SCV000296309 pathogenic not provided 2023-06-04 criteria provided, single submitter clinical testing The BRCA1 c.5266dup (p.Gln1756Profs*74) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature as a founder mutation in the Ashkenazi Jewish population and has been reported in multiple individuals and families affected with breast and/or ovarian cancer (PMIDs: 18694767 (2008), 19208665 (2009), 21119707 (2011), 30606148 (2019), 32438681 (2020), 35409996 (2022)), as well as prostate cancer (PMID: 36612302 (2023)). This variant has also been reported in affected and control individuals in a large-scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). A functional study showed that this variant caused the complete loss of BRCA1 phosphopeptide binding activity (PMID: 15133502 (2004)). Based on the available information, this variant is classified as pathogenic.
GeneKor MSA RCV000119097 SCV000296781 pathogenic Hereditary breast ovarian cancer syndrome 2021-01-09 criteria provided, single submitter clinical testing This mutation is an insertion of one nucleotide (cytosine), resulting in a frameshift and the creation of a novel translational termination codon after 74 amino acid residues. The protein product thus produced is truncated and non-functional. This mutation has been described in the international bibliography (http://research.nhgri.nih.gov/projects/bic) and has been shown to be a founder mutation in a number of ethnic groups (PMID: 12142080). This mutation has been described in the mutation database ClinVar (Variation ID:17677).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000019246 SCV000326231 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-10-02 criteria provided, single submitter clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000412924 SCV000492476 pathogenic Breast neoplasm criteria provided, single submitter research
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000415060 SCV000493028 pathogenic Neoplasm of ovary 2014-05-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000119097 SCV000494397 pathogenic Hereditary breast ovarian cancer syndrome 2016-04-22 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5266dupC variant results in a frameshift, which alters the protein's amino acid sequence beginning at position 1756 and leads to a premature termination codon 73 amino acids downstream. It is predicted to cause a truncated or absent BRCA1 protein due to non-sense meditated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (such as c.5387C>A/p.Ser1796X, c.5417delC/Pro1806fsX28, etc). Mutation Taster predicts a damaging outcome for this variant, and functional studies have shown HR activity is significantly impaired by this variant (Bouwman_BRCA1_Cancer Discovery_2013). BRCA1 c.5266dupC was found in 19/121412 control chromosomes at a frequency of 0.0001565, which does not exceed maximal expected frequency of a pathogenic BRCA1 allele (0.0010005). The variant has been cited in hundreds of HBOC patients and is reported as a known common founder mutation in the literature. Additionally, this variant has been classified by multiple clinical labs and databases as pathogenic. Taken together, this variant was classified as disease variant/pathogenic.
Baylor Genetics RCV000056287 SCV000540940 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Department of Medical Genetics, Oslo University Hospital RCV000019246 SCV000564336 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-07-01 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000119097 SCV000576438 pathogenic Hereditary breast ovarian cancer syndrome 2017-02-14 criteria provided, single submitter clinical testing
Genologica Medica RCV000019246 SCV000577937 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2017-01-01 criteria provided, single submitter clinical testing
Bioinformatics dept., Datar Cancer Genetics Limited, India RCV000495973 SCV000584019 pathogenic Punctate palmoplantar keratoderma type 2 2017-07-21 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000019246 SCV000584072 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-12-10 criteria provided, single submitter research
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000019246 SCV000743374 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2014-10-10 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000019246 SCV000744589 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-09-21 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000258962 SCV000778733 pathogenic not provided 2023-05-23 criteria provided, single submitter clinical testing PP5, PS4_moderate, PVS1
PreventionGenetics, part of Exact Sciences RCV004554607 SCV000806969 pathogenic BRCA1-related disorder 2024-02-26 criteria provided, single submitter clinical testing The BRCA1 c.5266dupC variant is predicted to result in a frameshift and premature protein termination (p.Gln1756Profs*74). This variant, also described as 5382insC, 5385insC, or 5329dupC in the literature, has been associated with autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC) (OMIM #604370; Bogdanova et al. 2010. PubMed ID: 20569256; Alemar et al. 2016. PubMed ID: 27425403; Azzollini et al. 2016. PubMed ID: 27062684; Hamel et al. 2011. PubMed ID: 21119707). This is a founder variant in the Ashkenazi Jewish population, identified in 0.13% of Ashkenazi Jewish individuals unselected for breast cancer (Roa et al. 1996. PubMed ID:8841191). This variant is frequently observed in the Ashkenazi Jewish population in gnomad. This variant is also found in individuals of diverse ancestry at variable frequencies. It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/17677/). Frameshift variants in BRCA1 are expected to be pathogenic. In summary, this variant is interpreted as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000019246 SCV000839893 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2017-05-25 criteria provided, single submitter clinical testing The c.5266dup (p.Gln1756Profs*74) variant in the BRCA1 gene has been detected multiple patients with breast cancer and/or ovarian cancer [PMID 7894492, 26718727, 20569256, 21503673, 23232912, 26666763, 22430266, 19359128, 20730485, 22032251, 21324516, among others, referred as 5382C in some publications], pancreatic cancer [PMID 24737347, 26440929] and prostate cancer [PMID 27433846 ]. This variant is a founder mutation in the Ashkenazi Jewish population and is found with a high prevalence in Poland and Eastern Europe [PMID 20569256, 20345474, 20507347]. The estimated risk for carriers of this variant was 89% for breast cancer and 42% for ovarian cancer by age 70 [PMID 22430266]. This one bp duplication in exon 19 results in a frameshift and the creation of a premature stop codon. This variant is thus predicted to result in a loss of function of the protein. This variant has been detected in 19 individuals from the ExAC database (http://exac.broadinstitute.org/variant/17-41209079-T-TG). This variant thus classified as pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000735471 SCV000901129 pathogenic Breast and/or ovarian cancer 2023-03-24 criteria provided, single submitter clinical testing
Mendelics RCV000019246 SCV001140476 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000258962 SCV001247342 pathogenic not provided 2024-02-01 criteria provided, single submitter clinical testing BRCA1: PVS1, PS4:Moderate
Institute of Human Genetics, University of Leipzig Medical Center RCV000019246 SCV001251420 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2024-02-20 criteria provided, single submitter clinical testing Criteria applied: PVS1,PS4,PM5_STR,PS3_MOD
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000056287 SCV001368385 pathogenic Familial cancer of breast 2019-06-03 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1.
Institute of Genomics, University of Tartu RCV000019246 SCV001430693 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 criteria provided, single submitter research
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000258962 SCV001447116 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital RCV000258962 SCV001449581 pathogenic not provided 2014-09-18 criteria provided, single submitter clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000019246 SCV001499705 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2020-04-02 criteria provided, single submitter clinical testing
Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar RCV000019246 SCV001519673 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000258962 SCV002009425 pathogenic not provided 2021-11-03 criteria provided, single submitter clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State RCV000119097 SCV002025907 pathogenic Hereditary breast ovarian cancer syndrome 2021-11-16 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV000019246 SCV002051788 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2021-10-29 criteria provided, single submitter clinical testing This BRCA1 variant (rs80357906) is rare (<0.1%) in a large population dataset (gnomAD: 51/282892 total alleles, 0.018%, no homozygotes) and has been reported in ClinVar. This frameshift variant results in a premature stop codon in exon 19 of 23 likely leading to nonsense-mediated decay and lack of protein production. This variant, also known as 5382insC and 5385insC in the literature, is a common cause of breast and ovarian cancer in the Ashkenazi Jewish population and has been reported in individuals from other ethnicities. This variant has been associated with a 67% to 89% risk of breast cancer by age 70, and a 33% to 42% risk of ovarian cancer by age 70. This variant was also identified in the patient's mother (JHG1740-2). We consider c.5266dupC to be pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000258962 SCV002058051 pathogenic not provided 2023-10-05 criteria provided, single submitter clinical testing The BRCA1 c.5266dup; p.Gln1756ProfsTer74 variant, also known as 5382insC, has been described in individuals and families with hereditary breast and ovarian cancer, peritoneal cancer, and pancreatic cancer and is a known pathogenic founder variant (Bogdanova 2010, Elsakov 2010, Heidemann 2012, Simard 1994, Uglanitsa 2010, Zhang 2011). This variant is reported as pathogenic in ClinVar (Variation ID: 17677). It is found in the general population with an overall allele frequency of 0.02% (51/282892 alleles) in the Genome Aggregation Database. This variant causes a frameshift by duplicating 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. [**Use the AJ BRCA template under BRCA NGS, OR Make sure to add the AJ recommendations from that template "If this individual is of Ashkenazi Jewish ancestry…"**] References: Bogdanova NV et al. High frequency and allele-specific differences of BRCA1 founder mutations in breast cancer and ovarian cancer patients from Belarus. Clin Genet. 2010 78(4):364-72. PMID: 20569256. Elsakov P et al. The contribution of founder mutations in BRCA1 to breast and ovarian cancer in Lithuania. Clin Genet. 2010 78(4):373-6. PMID: 20345474. Heidemann S et al. Double heterozygosity for mutations in BRCA1 and BRCA2 in German breast cancer patients: implications on test strategies and clinical management. Breast Cancer Res Treat. 2012 134(3):1229-39. PMID: 22535016. Simard J et al. Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families. Nat Genet. 1994 8(4):392-8. PMID: 7894492. Uglanitsa N et al. The contribution of founder mutations in BRCA1 to breast cancer in Belarus. Clin Genet. 2010 78(4):377-80. PMID: 20507347. 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. PMID: 21324516.
DASA RCV000019246 SCV002107076 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-03-05 criteria provided, single submitter clinical testing The c.5266dup;p.(Gln1756Profs*74) is a null frameshift variant (NMD) in the BRCA1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1_strong. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 17677; PMID: 15994883; PMID: 22430266) - PS4. The variant is present at low allele frequencies population databases (rs80357906 – gnomAD 0.001803%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV000019246 SCV002512516 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-12-13 criteria provided, single submitter clinical testing ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PP1 strong
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000258962 SCV002550948 pathogenic not provided 2024-02-06 criteria provided, single submitter clinical testing
Genetics and Molecular Pathology, SA Pathology RCV000019246 SCV002556792 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2021-08-23 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000019246 SCV002581822 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-09-06 criteria provided, single submitter clinical testing
Human Genetics Bochum, Ruhr University Bochum RCV000019246 SCV002758575 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-08-04 criteria provided, single submitter clinical testing ACMG criteria used to clasify this variant: PVS1, PM2, PS4
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000019246 SCV002762800 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-12-09 criteria provided, single submitter research PVS1, PS4_STR, BS1
Fulgent Genetics, Fulgent Genetics RCV002504809 SCV002813806 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S 2021-11-22 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000258962 SCV003811722 pathogenic not provided 2023-09-01 criteria provided, single submitter clinical testing
New York Genome Center RCV000019246 SCV003925393 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-01-28 criteria provided, single submitter clinical testing The c.5266dup (p.Gln1756ProfsTer74) variant identified in the BRCA1 gene is the duplication of a single nucleotide resulting in a frameshift at amino acid 1756/1863 (exon 19/23). This variant is predicted to incorporate a premature termination codon at approximately 74 amino acids downstream and result in either loss-of-function via nonsense mediated decay or protein truncation. This variant is found with low frequency in gnomAD(v3.1.2) (8 heterozygotes, 0 homozygotes; allele frequency: 1.972e-5), suggesting it is not a common benign variant in the populations represented in that database. The c.5266dup (p.Gln1756ProfsTer74) variant is reported in ClinVar as Pathogenic by an expert panel (VarID: 17677), and is one of the most frequently reported pathogenic variants in the BRCA1 gene. This variant has been reported in multiple affected individuals in the literature [PMID: 21119707, 24797986, 31706072, others]. Based on the available evidence c.5266dup(p.Gln1756ProfsTer74) variant is reported as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV000056287 SCV003925649 pathogenic Familial cancer of breast 2024-01-12 criteria provided, single submitter clinical testing Criteria applied: PVS1,PS4,PM5_STR,PS3_MOD
Illumina Laboratory Services, Illumina RCV000019246 SCV004014748 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2023-05-18 criteria provided, single submitter clinical testing The BRCA1 c.5266dup (p.Gln1756ProfsTer74) variant, also referred to as c.5382insC or c.5382_5383insC, causes a shift in the translational reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been previously identified in individuals with breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer (PMID: 29335925; PMID: 29961768; PMID: 11802209; PMID: 29492181; PMID: 22430266). Further, this variant is one of three well-characterized founder variants in the Ashkenazi Jewish population, accounting for an estimated 26% of pathogenic variants detected in this population (GeneReviews PMID: 20301425). The highest frequency of this allele in the Genome Aggregation Database is 0.002314 in the Ashkenazi Jewish population (v2.1.1). This variant has been classified as pathogenic by >60 submitters in ClinVar, including a BRCA1 expert panel. Based on the available evidence, the c.5266dup (p.Gln1756ProfsTer74) variant is classified as pathogenic for hereditary breast and ovarian cancer.
Baylor Genetics RCV000019246 SCV004212667 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2023-10-31 criteria provided, single submitter clinical testing
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg RCV000258962 SCV004231809 pathogenic not provided 2024-01-17 criteria provided, single submitter clinical testing This variant has been identified by standard clinical testing. female patient with metastatic breast cancer Selected ACMG criteria: Pathogenic (I):PP5;PS4;PVS1
Institute of Immunology and Genetics Kaiserslautern RCV000019246 SCV004363615 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2024-02-02 criteria provided, single submitter clinical testing ACMG Criteria: PM2_P; Variant was found in heterozygous state
Clinical Genomics Laboratory, Washington University in St. Louis RCV000019246 SCV005045105 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2024-03-11 criteria provided, single submitter clinical testing The BRCA1 c.5266dup (p.Gln1756Profs*74) variant is one of the most common variants reported in Central and Eastern European families with high risk of breast and/or ovarian cancer (Janavicius R, PMID: 23199084). This variant causes a frameshift by inserting one nucleotide, leading to a premature termination codon, which is predicted to lead to nonsense mediated decay. This variant has been reported in the ClinVar database as a germline pathogenic variant by 10 submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet RCV000019246 SCV005045968 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2024-05-27 criteria provided, single submitter clinical testing PVS1; PM5_PTC_Strong
OMIM RCV000019246 SCV000039534 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2008-10-15 no assertion criteria provided literature only
OMIM RCV000019247 SCV000053476 risk factor Pancreatic cancer, susceptibility to 2008-10-15 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000019246 SCV000053833 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2014-04-08 no assertion criteria provided clinical testing
GeneReviews RCV000119097 SCV000086949 not provided Hereditary breast ovarian cancer syndrome no assertion provided literature only Founder variant in Ashkenazi Jews; accounts for 26% of pathogenic variants in this population
Breast Cancer Information Core (BIC) (BRCA1) RCV000019246 SCV000145419 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2002-05-29 no assertion criteria provided clinical testing
Pathway Genomics RCV000019246 SCV000189885 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2014-07-24 no assertion criteria provided clinical testing
Institute of Human Genetics, Medical University Innsbruck RCV000019246 SCV000212010 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-02-11 no assertion criteria provided clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare RCV000056287 SCV000484933 pathogenic Familial cancer of breast no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto RCV000119097 SCV000587484 pathogenic Hereditary breast ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001353680 SCV000591601 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000258962 SCV000607156 not provided not provided no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000019246 SCV000733591 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 no assertion criteria provided clinical testing
True Health Diagnostics RCV000131328 SCV000805234 pathogenic Hereditary cancer-predisposing syndrome 2018-04-27 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735471 SCV000863608 pathogenic Breast and/or ovarian cancer 2016-07-07 no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV000415060 SCV000923779 pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research
CZECANCA consortium RCV000735471 SCV001451781 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute RCV000258962 SCV001906306 pathogenic not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000258962 SCV002036964 pathogenic not provided no assertion criteria provided clinical testing
Genetic Services Laboratory, University of Chicago RCV000019246 SCV002065769 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-01-10 no assertion criteria provided clinical testing DNA sequence analysis of the BRCA1 gene demonstrated a single base pair duplication in exon 19, c.5266dup. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 74 amino acids downstream of the change, p.Gln1756Profs*74. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated BRCA1 protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a frequency of 0.23% in the Ashkenazi Jewish subpopulation (dbSNP rs1217805587). This pathogenic sequence change is a well-described pathogenic BRCA1 variant and a known founder mutation in the Ashkenazi Jewish population reported in multiple individuals with hereditary breast and ovarian cancer syndrome (PMID: 12473589, 15131399, 9042909, 22430266, 24764757, 26976419). The c.5266dup sequence change is also referred to as 5382insC in the scientific literature
BRCAlab, Lund University RCV000019246 SCV002588831 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-08-26 no assertion criteria provided clinical testing
CZECANCA consortium RCV003128129 SCV003804343 pathogenic Endometrial carcinoma 2023-02-21 no assertion criteria provided clinical testing
Medical Genetics, Medical University Pleven RCV000019246 SCV004100884 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 no assertion criteria provided research

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