Submissions for variant NM_007294.4(BRCA1):c.5075-1G>C

dbSNP: rs1800747

Total submissions: 6

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	RCV000112486	SCV000326143	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001036909	SCV001200297	pathogenic	Hereditary breast ovarian cancer syndrome	2022-10-24	criteria provided, single submitter	clinical testing	Disruption of this splice site has been observed in individual(s) with a personal and/or family history of breast and ovarian cancer (PMID: 29446198, 30287823). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 16 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. ClinVar contains an entry for this variant (Variation ID: 125759). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Arg1699Trp, p.Leu1705Pro) have been determined to be pathogenic (PMID: 10811118, 11157798, 21473589, 26951538, 30209399; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Studies have shown that disruption of this splice site results in skipping of exon 17 (also known as exon 18), but is expected to preserve the integrity of the reading-frame (PMID: 24667779). Experimental studies have shown that disruption of this splice site affects BRCA1 function (PMID: 30209399). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant.
Ambry Genetics	RCV003298139	SCV003995314	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-06	criteria provided, single submitter	clinical testing	The c.5075-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 16 of the BRCA1 gene. 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). RNA studies have shown this alteration to result in the in-frame skipping of coding exon 16 (exon 18 in the literature) and the impacted region is critical for protein function (Ambry internal data; Steffensen AY et al. Eur J Hum Genet, 2014 Dec;22:1362-8). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Baylor Genetics	RCV000112486	SCV004215135	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-09	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112486	SCV000145297	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112486	SCV001244049	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro