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

dbSNP: rs80357906

Total submissions: 79

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	2021-07-07	criteria provided, single submitter	clinical testing	The c.5266dupC pathogenic mutation, located in coding exon 18 of the BRCA1 gene, results from a duplication of C at nucleotide position 5266, causing a translational frameshift with a predicted alternate stop codon (p.Q1756Pfs*74). 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 P et al. Am. J. Hum. Genet. 1999 Apr;64:963-70; Hamel N et al. Eur. J. Hum. Genet. 2011 Mar;19:300-6; Kluz T et al. Hered Cancer Clin Pract. 2018 Feb;16:6). This mutation has been reported in individuals with hereditary breast and ovarian cancer (HBOC) syndrome, including individuals with male breast cancer, pancreatic cancer, and prostate cancer (Antoniou AC et al. J. Med. Genet. 2005 Jul;42:602-3; Bogdanova NV et al. Clin. Genet. 2010 Oct;78(4):364-72; Finkelman BS et al J Clin Oncol. 2012 Apr;30(12):1321-8; Bernards SS et al. Gynecol Oncol. 2016 Feb;140(2):221-5; Pritchard CC et al. N Engl J Med. 2016 Aug;375(5):443-53; Kluz T et al. Hered Cancer Clin Pract. 2018 Mar;16:6; Fostira F et al. Breast Cancer Res Treat. 2018 May;169(1):105-113; Yurgelun MB et al. Genet Med. 2019 Jan;21(1):213-223). In a large case control-study, this variant was reported in 97/60,466 breast cancer cases and in 11/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Of note, this alteration is also designated as 5382insC and 5385insC in the 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	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	2019-04-24	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, Elwad 2011, Breast Cancer Information Core (BIC) database). This variant has also been identified in 24/103702 Ashkenazi Jewish and 25/129200 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397507247). 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.Gln1756fs variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282341.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein and presence in affected individuals. 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	RCV003389670	SCV000806969	pathogenic	BRCA1-related condition	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.
Mendelics	RCV000119097	SCV000839212	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
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
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