Submissions for variant NM_007294.4(BRCA1):c.5278-2A>G

dbSNP: rs397509253

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000258354	SCV000326245	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001023845	SCV001185776	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-08	criteria provided, single submitter	clinical testing	The c.5278-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 19 in the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. One functional study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496299	SCV001588795	pathogenic	Hereditary breast ovarian cancer syndrome	2020-10-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that variants in this splice site are associated with skipping of exon 20 and skipping of 8 bp at the 5'-end of exon 20, which introduce frameshift (PMID: 23239986, 23451180). The resulting mRNA is expected to undergo nonsense-mediated decay. Exon 20 is also known as exon 21 in the literature. Experimental studies have shown that this variant affects BRCA1 protein function (PMID: 30209399). This variant has not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 267593). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 19 of the BRCA1 gene. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496299	SCV000587486	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000258354	SCV001243036	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro