Total submissions: 81
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Evidence- |
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. |
| Labcorp Genetics |
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, |
RCV000019246 | SCV000195938 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2014-11-03 | criteria provided, single submitter | clinical testing | |
| Gene |
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, |
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 |
RCV000258962 | SCV000226938 | pathogenic | not provided | 2014-11-07 | criteria provided, single submitter | clinical testing | |
| Laboratory for Molecular 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, |
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. |
| Gene |
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 |
RCV000019246 | SCV000326231 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2015-10-02 | criteria provided, single submitter | clinical testing | |
| A. |
RCV000412924 | SCV000492476 | pathogenic | Breast neoplasm | criteria provided, single submitter | research | ||
| Centre for Mendelian Genomics, |
RCV000415060 | SCV000493028 | pathogenic | Ovarian neoplasm | 2014-05-29 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
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, |
RCV000019246 | SCV000564336 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2015-07-01 | criteria provided, single submitter | clinical testing | |
| Institute for Biomarker Research, |
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. |
RCV000495973 | SCV000584019 | pathogenic | Punctate palmoplantar keratoderma type 2 | 2017-07-21 | criteria provided, single submitter | clinical testing | |
| Hudson |
RCV000019246 | SCV000584072 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2015-12-10 | criteria provided, single submitter | research | |
| Genome Diagnostics Laboratory, |
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, |
RCV000019246 | SCV000744589 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2015-09-21 | criteria provided, single submitter | clinical testing | |
| Mayo Clinic Laboratories, |
RCV000258962 | SCV000778733 | pathogenic | not provided | 2023-05-23 | criteria provided, single submitter | clinical testing | PP5, PS4_moderate, PVS1 |
| Human Genome Sequencing Center Clinical Lab, |
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, |
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 | |
| Ce |
RCV000258962 | SCV001247342 | pathogenic | not provided | 2024-07-01 | criteria provided, single submitter | clinical testing | BRCA1: PVS1, PS4:Moderate |
| Institute of Human Genetics, |
RCV000019246 | SCV001251420 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2024-04-30 | criteria provided, single submitter | clinical testing | Criteria applied: PVS1,PS4,PM5_STR |
| Centre for Mendelian Genomics, |
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, |
RCV000019246 | SCV001430693 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | criteria provided, single submitter | research | ||
| Institute of Medical Genetics and Applied Genomics, |
RCV000258962 | SCV001447116 | pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
| Clinical Genetics and Genomics, |
RCV000258962 | SCV001449581 | pathogenic | not provided | 2014-09-18 | criteria provided, single submitter | clinical testing | |
| Department of Molecular Diagnostics, |
RCV000019246 | SCV001499705 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2020-04-02 | criteria provided, single submitter | clinical testing | |
| Biomedical Genomics and Oncogenetics Laboratory, |
RCV000019246 | SCV001519673 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | criteria provided, single submitter | clinical testing | ||
| Institute for Clinical Genetics, |
RCV000258962 | SCV002009425 | pathogenic | not provided | 2021-11-03 | criteria provided, single submitter | clinical testing | |
| National Health Laboratory Service, |
RCV000119097 | SCV002025907 | pathogenic | Hereditary breast ovarian cancer syndrome | 2021-11-16 | criteria provided, single submitter | clinical testing | |
| Johns Hopkins Genomics, |
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, |
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, |
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, |
RCV000258962 | SCV002550948 | pathogenic | not provided | 2024-07-31 | criteria provided, single submitter | clinical testing | |
| Genetics and Molecular 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, |
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, |
RCV000019246 | SCV002762800 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2022-12-09 | criteria provided, single submitter | research | PVS1, PS4_STR, BS1 |
| 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, |
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, |
RCV000056287 | SCV003925649 | pathogenic | Familial cancer of breast | 2024-09-30 | criteria provided, single submitter | clinical testing | Criteria applied: PVS1,PS4,PM5_STR |
| Illumina Laboratory Services, |
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 | 2024-03-17 | criteria provided, single submitter | clinical testing | |
| Institute of Human Genetics, |
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, |
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, |
RCV000019246 | SCV005045968 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2024-05-27 | criteria provided, single submitter | clinical testing | PVS1; PM5_PTC_Strong |
| Clinical Genetics Laboratory, |
RCV000258962 | SCV005199697 | pathogenic | not provided | 2024-03-18 | criteria provided, single submitter | clinical testing | |
| 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 |
RCV000019246 | SCV000053833 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2014-04-08 | no assertion criteria provided | clinical testing | |
| Gene |
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 |
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, |
RCV000019246 | SCV000212010 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2015-02-11 | no assertion criteria provided | clinical testing | |
| Bioscientia Institut fuer Medizinische Diagnostik Gmb |
RCV000056287 | SCV000484933 | pathogenic | Familial cancer of breast | no assertion criteria provided | clinical testing | ||
| Research Molecular Genetics Laboratory, |
RCV000119097 | SCV000587484 | pathogenic | Hereditary breast ovarian cancer syndrome | 2014-01-31 | no assertion criteria provided | research | |
| Department of Pathology and Laboratory Medicine, |
RCV001353680 | SCV000591601 | uncertain significance | Malignant tumor of breast | no assertion criteria provided | clinical testing | ||
| Genome |
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, |
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 | |
| Prevention |
RCV004554607 | SCV000806969 | pathogenic | BRCA1-related disorder | 2024-06-26 | no assertion criteria provided | 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) has been reported in multiple individuals 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). It is a founder variant in the Ashkenazi Jewish population and is reported in 0.23% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. 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. |
| Foulkes Cancer Genetics LDI, |
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, |
RCV000415060 | SCV000923779 | pathogenic | Ovarian neoplasm | 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, |
RCV000258962 | SCV001906306 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Laboratory of Diagnostic Genome Analysis, |
RCV000258962 | SCV002036964 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Genetic Services Laboratory, |
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, |
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, |
RCV000019246 | SCV004100884 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion criteria provided | research |