ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5406+4A>G (rs397509279)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000256115 SCV000322145 likely pathogenic not provided 2015-07-23 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5406+4A>G or IVS21+4A>G and consists of a A>G nucleotide substitution at the +4 position of intron 21 of the BRCA1 gene. Multiple in silico models predict this variant to damage or destroy the nearby natural donor site, and to possibly cause abnormal gene splicing. This variant, published as IVS22+4A>G using alternate intron numbering, was identified in two relatives affected by ovarian cancer and in vitro analysis demonstrated exclusion of exon 22 (Wappenschmidt 2012). The adenine (A) nucleotide that is altered is conserved across species. Based on the currently available information, we consider BRCA1 c.5406+4A>G to be a likely pathogenic variant.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000256115 SCV000600419 pathogenic not provided 2016-09-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV001024049 SCV001186002 pathogenic Hereditary cancer-predisposing syndrome 2019-06-06 criteria provided, single submitter clinical testing The c.5406+4A>G intronic variant results from an A to G substitution 4 nucleotides after coding exon 20 in the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; and multiple studies with patient-derived RNA showed that the cDNA had skipping of coding exon 20 (also known as Exon 22) leading to a frameshift with predicted premature termination codon (Wappenschmidt B et al. PLoS ONE, 2012 Dec;7:e50800; Kraus C et al. Int. J. Cancer, 2017 Jan;140:95-102). A similar alteration, BRCA1 c.5406+5C>G was shown to have the same splice defect (Houdayer C et al. Hum. Mutat., 2012 Aug;33:1228-38). Another functional study found that this nucleotide substitution is deleterious in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation.
Color Health, Inc RCV001024049 SCV001357539 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-02 criteria provided, single submitter clinical testing
Brotman Baty Institute,University of Washington RCV001072852 SCV001238306 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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.