Submissions for variant NM_007294.4(BRCA1):c.4987-1G>A

dbSNP: rs730881495

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000172806	SCV000282242	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-03	reviewed by expert panel	curation	Allele-specific assay on patient-derived mRNA demonstrated that the variant allele produces only predicted non-functional transcripts. Variant allele produces r.4987_5074del transcript (encoding predicted non-functional protein).
GeneDx	RCV000159998	SCV000210192	pathogenic	not provided	2017-04-05	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.4987-1G>A or IVS15-1G>A and consists of a G>A nucleotide substitution at the -1 position of intron 15 of the BRCA1 gene. Using alternate nomenclature, this variant would be defined as BRCA1 5106-1G>A, IVS16-1G>A. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been shown to cause skipping of exon 17 (exon 16 using internal nomenclature) by RT-PCR studies (Colombo 2013). Based on the current evidence, we consider this variant to be pathogenic.
Pathway Genomics	RCV000172806	SCV000223752	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-10-30	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000172806	SCV000326092	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000508328	SCV000602673	pathogenic	not specified	2016-08-19	criteria provided, single submitter	clinical testing
Counsyl	RCV000172806	SCV000677759	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-03-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000694301	SCV000822739	pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-23	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 15 of the BRCA1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 26681312). This variant is also known as IVS16-1G>A. ClinVar contains an entry for this variant (Variation ID: 182165). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 23451180). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001178132	SCV001342501	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-09	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the -1 position of intron 15 of the BRCA1 gene. An RNA study has shown that this variant causes out-of-frame skipping of exon 16, resulting in premature truncation (PMID: 23451180). A functional study has shown that this variant impacts BRCA1 function in a human haploid cell proliferation assay (PMID: 30209399). This variant has been detected in an individual affected with breast cancer, a family suspected of hereditary breast and ovarian cancer and a family among CIMBA participants (PMID: 23451180, 26681312, 29446198). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Ambry Genetics	RCV001178132	SCV002645638	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-18	criteria provided, single submitter	clinical testing	The c.4987-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 15 of the BRCA1 gene. This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet Med, 2016 08;18:823-32). 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 10;562:217-222). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). Two other alterations impacting the same acceptor site (c.4987-1G>A and c.4987-2A>C) have been described as non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;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. In addition to the clinical data presented in the literature, 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.
Brotman Baty Institute, University of Washington	RCV000172806	SCV001238411	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro