ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5266dupC (p.Gln1756Profs) (rs80357906)

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Total submissions: 46
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000412924 SCV000492476 pathogenic Neoplasm of the breast criteria provided, single submitter research
Ambry Genetics RCV000131328 SCV000186302 pathogenic Hereditary cancer-predisposing syndrome 2017-06-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Baylor Genetics RCV000056287 SCV000540940 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Bioinformatics dept.,Datar Cancer Genetics Limited, India RCV000495973 SCV000584019 pathogenic Porokeratosis punctata palmaris et plantaris 2017-07-21 criteria provided, single submitter clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000056287 SCV000484933 pathogenic Familial cancer of breast no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000019246 SCV000145419 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000119097 SCV000219263 pathogenic Hereditary breast and ovarian cancer syndrome 2017-02-02 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000735471 SCV000901129 pathogenic Breast and/or ovarian cancer 2017-05-25 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415060 SCV000493028 pathogenic Neoplasm of ovary 2014-05-29 criteria provided, single submitter clinical testing
Color RCV000131328 SCV000292125 pathogenic Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000019246 SCV000326231 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000019246 SCV000220482 pathogenic Breast-ovarian cancer, familial 1 2014-07-07 criteria provided, single submitter literature only
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000019246 SCV000744589 pathogenic Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000019246 SCV000564336 pathogenic Breast-ovarian cancer, familial 1 2015-07-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000119097 SCV000591601 pathogenic Hereditary breast and ovarian cancer syndrome 2016-08-30 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000019246 SCV000733591 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing
Division Human Genetics,Medical University Innsbruck RCV000019246 SCV000212010 pathogenic Breast-ovarian cancer, familial 1 2015-02-11 no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000258962 SCV000226938 pathogenic not provided 2014-11-07 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000019246 SCV000282341 pathogenic Breast-ovarian cancer, familial 1 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
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
GeneDx RCV000258962 SCV000209886 pathogenic not provided 2016-12-30 criteria provided, single submitter clinical testing This duplication of one nucleotide is denoted BRCA1 c.5266dupC at the cDNA level and p.Gln1756ProfsX74 (Q1756PfsX74) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ATCC[dupC]AGGA. The duplication causes a frameshift, which changes a Glutamine to a Proline at codon 1756, and creates a premature stop codon at position 74 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation. BRCA1 c.5266dupC, also known as 5382insC or 5385insC using alternate nomenclature, is a common founder variant in the Ashkenazi Jewish population (Roa 1996). We consider this variant to be pathogenic.
GeneDx RCV000056287 SCV000210056 pathogenic Familial cancer of breast 2014-10-09 criteria provided, single submitter clinical testing This insertion of one nucleotide is denoted BRCA1 c.5266insC (a.k.a c.5266dupC) at the cDNA level and p.Gln1756ProfsX74 (Q1756PfsX74) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TCCC{insC}AGGA. The inserton causes a frameshift, which changes a Glutamine to a Proline at codon 1756 in exon 19, and creates a premature stop codon at position 74 of the new reading frame. This mutation is predicted to cause loss of normal protein function through protein truncation. BRCA1 c.5266_5267insC (a.k.a 5266dupC), also known as 5382insC or 5385insC using alternate nomenclature, is a common founder mutation in the Ashkenazi Jewish population (Roa 1996). We consider this mutation to be pathogenic. and is indicative of Hereditary Breast and Ovarian Cancer (HBOC), an autosomal dominant condition that predisposes to early onset breast cancer, ovarian and fallopian tube cancer, as well as other cancers. Breast and ovarian cancer are the predominant BRCA1-related cancers that unaffected female mutation carriers are at risk to develop. The lifetime risk for breast cancer is estimated to be 57 to 84% and the lifetime risk for ovarian cancer is estimated to be 24 to 54% (Antoniou 2003, Chen 2007, Ford 1998). BRCA1 mutations have also been reported in women with fallopian tube carcinoma, primary peritoneal carcinoma, and uterine serous carcinoma (Levine 2003, Pennington 2013). Graeser et al. (2009) found that women who harbor pathogenic BRCA1 or 2 mutations have an increased risk for contralateral breast cancer that is dependent on age at initial diagnosis. It is estimated that the risk to develop a second breast cancer within 10 years of the first diagnosis if initially diagnosed less than age 40 years of age is 21 to 31%, between the ages of 40 and 50 is 11 to 13% and after the age of 50 is 8%. Additionally, it is estimated that the risk to develop a second breast cancer within 25 years of their first diagnosis if initially diagnosed less than 40 years of age is 63%, between the ages of 40 and 50 is 44 to 49% and after the age of 50 is 20%. Other cancer risks associated with a BRCA1 pathogenic variant include approximately a 20% risk for prostate cancer in male carriers (Thompson 2002), a 4% risk for male breast cancer (Liede 2004), and an estimated 1 to 3% risk for pancreatic cancer in both men and women (Brose 2002, Thompson 2002). The variant is found in BRCA-AJ,BRCA1-BRCA2,BR-OV-HEREDIC,HEREDICANCER,ENDOM-HEREDIC,HIRISK-BR-HEREDIC panel(s).
GeneKor MSA RCV000119097 SCV000296781 pathogenic Hereditary breast and ovarian cancer syndrome 2018-08-01 criteria provided, single submitter clinical testing
GeneReviews RCV000056287 SCV000086949 pathologic Familial cancer of breast 2013-09-26 no assertion criteria provided curation Converted during submission to Pathogenic.
Genetic Services Laboratory, University of Chicago RCV000019246 SCV000593675 pathogenic Breast-ovarian cancer, familial 1 2016-05-16 criteria provided, single submitter clinical testing
Genologica Medica RCV000019246 SCV000577937 pathogenic Breast-ovarian cancer, familial 1 2017-01-01 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000019246 SCV000743374 pathogenic Breast-ovarian cancer, familial 1 2014-10-10 criteria provided, single submitter 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.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785211 SCV000923779 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000019246 SCV000584072 pathogenic Breast-ovarian cancer, familial 1 2015-12-10 criteria provided, single submitter research
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000019246 SCV000839893 pathogenic Breast-ovarian cancer, familial 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.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000119097 SCV000576438 pathogenic Hereditary breast and ovarian cancer syndrome 2017-02-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000119097 SCV000494397 pathogenic Hereditary breast and 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.
Invitae RCV000119097 SCV000076906 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-01 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 19 of the BRCA1 mRNA (c.5266dupC), causing a frameshift at codon 1756. This creates a premature translational stop signal in the last exon of the BRCA1 mRNA (p.Gln1756Profs*74). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the final 73 amino acids of the protein, which includes the C-terminal BRCT domain. This pathogenic variant is a common cause of breast and ovarian cancer in the Ashkenazi Jewish population (PMID: 9042909, 22430266), and has been reported in individuals from other ethnicities (PMID: 22185575). This variant is also known as 5382insC and 5385insC in the literature. 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). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000119097 SCV000271320 pathogenic Hereditary breast and ovarian cancer syndrome 2016-12-02 criteria provided, single submitter clinical testing The p.Gln1756fs variant in BRCA1 (also referred to as p.Gln1777fs) is a founder variant in the Ashkenazi Jewish population and has been reported in >1000 indivi duals with BRCA1-associated cancers (Abeliovich 1997, Elwad 2011, Breast Cancer Information Core (BIC) database). This variant has also been identified in 22/10 152 Ashkenazi Jewish and 20/126734 European chromosomes by the Genome Aggregatio n Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397507247). This v ariant 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 trunca ted or absent protein. Heterozygous loss of function of the BRCA1 gene is an est ablished disease mechanism in hereditary breast and ovarian cancer (HBOC). Furth ermore, the p.Gln1756fs variant was classified as Pathogenic on April 22, 2016 b y the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282341.1). In summary, the p.Gln1756fs variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein a nd presence in affected individuals. ACMG/AMP Criteria applied: PS4, PVS1 (Richa rds 2015).
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000258962 SCV000778733 pathogenic not provided 2016-12-21 no assertion criteria provided clinical testing
Mendelics RCV000119097 SCV000839212 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000019246 SCV000195938 pathogenic Breast-ovarian cancer, familial 1 2014-11-03 criteria provided, single submitter clinical testing
OMIM RCV000019246 SCV000039534 pathogenic Breast-ovarian cancer, familial 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
Pathway Genomics RCV000019246 SCV000189885 pathogenic Breast-ovarian cancer, familial 1 2014-07-24 no assertion criteria provided clinical testing
PreventionGenetics RCV000258962 SCV000806969 pathogenic not provided 2016-10-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000258962 SCV000296309 pathogenic not provided 2015-03-16 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000119097 SCV000587484 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000019246 SCV000053833 pathogenic Breast-ovarian cancer, familial 1 2014-04-08 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

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