ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5470_5477delATTGGGCA (p.Ile1824Aspfs) (rs80357973)

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Total submissions: 9
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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) RCV000112668 SCV000300263 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000049010 SCV000077023 pathogenic Hereditary breast and ovarian cancer syndrome 2018-08-15 criteria provided, single submitter clinical testing This sequence change deletes 8 nucleotides from exon 23 of the BRCA1 mRNA (c.5470_5477delATTGGGCA), causing a frameshift at codon 1824. This creates a premature translational stop signal in the last exon of the BRCA1 mRNA (p.Ile1824Aspfs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 40 amino acids of the BRCA1 protein. This variant has been reported in several individuals affected with breast and/or ovarian cancer (PMID: 25366075, 15117986, 25863477, 26824983, 16455195, 26848529, 26852015, 27257965). This variant is also known as 5589del8 in the literature. ClinVar contains an entry for this variant (Variation ID: 55591). A different truncation downstream of this variant (p.Arg1835*) has been determined to be pathogenic (PMID: 8554067, 24504028, 16683254). This suggests that deletion of this region of the BRCA1 protein is causative of disease. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131859 SCV000186914 pathogenic Hereditary cancer-predisposing syndrome 2017-12-27 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)
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240711 SCV000265867 pathogenic Neoplasm of the breast 2015-11-01 criteria provided, single submitter research
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000112668 SCV000326329 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000480110 SCV000565822 pathogenic not provided 2016-08-22 criteria provided, single submitter clinical testing This deletion of eight nucleotides in BRCA1 is denoted c.5470_5477delATTGGGCA at the cDNA level and p.Ile1824AspfsX3 (I1824DfsX3) at the protein level. The normal sequence, with the bases that are deleted in braces, is AGCA[ATTGGGCA]GATG. The deletion causes a frameshift, which changes an Isoleucine to an Aspartic Acid at codon 1824, and creates a premature stop codon at position 3 of the new reading frame. Even though this frameshift occurs in the last exon of the gene, and nonsense-mediated decay is not expected to occur, it is significant since the last 40 amino acids are no longer translated, disrupting the BRCT2 domain. This variant is predicted to cause loss of normal protein function through protein truncation. Also reported as BRCA1 5589del8 or 5589_5596delATTGGGCA using alternate nomenclature, this variant has been reported in individuals with a personal and/or family history of early-onset breast and/or ovarian cancer and is a recurrent pathogenic variant in the Chinese population (Choi 2004, Ahn 2007, Hu 2007, Li 2008, Kim 2014, Cao 2016). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000480110 SCV000600424 pathogenic not provided 2017-04-14 criteria provided, single submitter clinical testing
3DMed Clinical Laboratory Inc RCV000240711 SCV000803962 pathogenic Neoplasm of the breast 2017-11-20 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112668 SCV000145533 pathogenic Breast-ovarian cancer, familial 1 2002-06-20 no assertion criteria provided clinical testing

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