ClinVar Miner

Submissions for variant NM_007299.4(BRCA1):c.*83del (rs886039675)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254704 SCV000322615 likely pathogenic not provided 2017-12-26 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA1 is denoted c.5569delC at the cDNA level and p.Gln1857ArgfsX65 (Q1857RfsX65) at the protein level. The normal sequence, with the base that is deleted in brackets, is ACCC[delC]AGAT. Using alternate nomenclature, this variant would be defined as BRCA1 5688delC, and has not, to our knowledge, been reported in the literature. The deletion causes a frameshift which changes a Glutamine to an Arginine at codon 1857 in the last exon of the gene, and results in an extension of the protein. The last seven amino acids are replaced with 64 incorrect amino acids, disrupting a region known to interact with multiple proteins (Paul 2014). Based on currently available evidence, we consider this deletion to be a likely pathogenic variant.
Invitae RCV000465890 SCV000549427 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-03-28 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 23 of the BRCA1 mRNA (c.5569delC), causing a frameshift at codon 1857. This is expected to delete the last 7 amino acids of the BRCA1 protein and replace them with 64 additional amino acid residues, creating a new downstream translational stop signal in the last exon that extends the length of the protein (p.Gln1857Argfs*65). While this is not anticipated to result in nonsense mediated decay, it may result in a disrupted BRCA1 protein. This variant is not present in population databases (ExAC no frequency). This variant was found to segregate with a BRCA1-related disease in a family (Invitae), and has been reported in an individual in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 265622). The frameshift caused by this variant affects the C-terminal end of the BRCA1 protein partially including the BRCT domain (residues 1646-1859), which is important for DNA repair activity (PMID: 11573086, 14576433, 15133503, 25652403). While a protein structural change is likely expected, functional studies have not been done to test whether or not this variant affects protein function. In summary, this is a rare frameshift variant that has been observed to segregate with disease in a family with a BRCA1-related disease. In the absence of additional genetic/functional data, it has been classified as Likely Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000465890 SCV000699273 likely pathogenic Hereditary breast and ovarian cancer syndrome 2017-05-15 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5569delC (p.Gln1857Argfs) variant results in a frame-shift change, predicted to cause a replacement of the last 7 amino acids with 64 incorrect amino acids. Non-sense mediated mRNA decay may not happen since this variant is close the C-terminus. This alteration affects the c-terminus, including part of the BCRT domain, which is important for DNA repair activity. One in silico tool predicts a benign outcome for this variant. This variant is absent in 121000 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.