ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.844_850dup (p.Gln284fs) (rs80357989)

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Total submissions: 12
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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) RCV000112803 SCV000323920 pathogenic Breast-ovarian cancer, familial 1 2016-10-18 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000165711 SCV000216452 pathogenic Hereditary cancer-predisposing syndrome 2014-09-10 criteria provided, single submitter clinical testing The c.844_850dupTCATTAC pathogenic mutation (also known as 969ins7 and 970ins7), located in coding exon 9 of the BRCA1 gene, results from a duplication of 7 nucleotides at positions 844-850, causing a translational frameshift with a predicted alternate stop codon. This mutation was first reported in one individual from a series of Canadian high-risk breast/ovarian cancer families (Ozcelik H, J. Med. Genet. 2003 Aug; 40(8):e91). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000505835 SCV000296400 pathogenic not provided 2015-10-17 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000112803 SCV000326443 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414853 SCV000492787 pathogenic Rhabdomyosarcoma (disease) 2015-08-10 criteria provided, single submitter clinical testing
GeneDx RCV000505835 SCV000779139 pathogenic not provided 2017-10-30 criteria provided, single submitter clinical testing This duplication of seven nucleotides in BRCA1 is denoted c.844_850dupTCATTAC at the cDNA level and p.Gln284LeufsX5 (Q284LfsX5) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is CAGC[dupTCATTAC]AGCA. The duplication causes a frameshift which changes a Glutamine to a Leucine at codon 284, and creates a premature stop codon at position 5 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.844_850dupTCATTAC, previously published as 969ins7 using alternate nomenclature, has been reported in multiple individuals with hereditary breast and/or ovarian cancer and is described as a recurrent variant in the Slovenian population (Stegel 2011, Navokovic 2012, Dobricic 2013, Karami 2013, Cini 2016, Cvelbar 2017). We consider this variant to be pathogenic.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000112803 SCV001499626 pathogenic Breast-ovarian cancer, familial 1 2020-04-02 criteria provided, single submitter clinical testing
Invitae RCV000496599 SCV001591510 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln284Leufs*5) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 12920083, 26306726, 16287141, 23635950, 22923021, 28740454) and in an individual affected with pancreatic ductal adenocarcinoma (PMID: 25940717). The variant is also known as 970ins7, 969insTCATTAC, 969ins7, and 850_851insTCATTAC in the literature. ClinVar contains an entry for this variant (Variation ID: 55735). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000165711 SCV001736476 pathogenic Hereditary cancer-predisposing syndrome 2020-06-29 criteria provided, single submitter clinical testing This variant inserts 7 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 969ins7 and 970ins7 in the literature. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 12920083, 23635950, 26852130) including recurrent affected families in Slovenia (PMID: 22923021). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112803 SCV000145704 pathogenic Breast-ovarian cancer, familial 1 1998-11-17 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496599 SCV000587081 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000505835 SCV001552030 uncertain significance not provided no assertion criteria provided clinical testing

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