Submissions for variant NM_007294.4(BRCA1):c.4986+4A>C

dbSNP: rs80358087

Total submissions: 11

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	RCV000031200	SCV000326081	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000480773	SCV000569472	likely pathogenic	not provided	2017-02-14	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.4986+4A>C or IVS15+4A>C and consists of an A>C nucleotide substitution at the +4 position of intron 15 of the BRCA1 gene. Using alternate nomenclature, this variant would be defined as BRCA1 5105+4A>C or IVS16+4A>C. Multiple in silico models predict this variant to destroy the nearby natural donor site and to possibly cause abnormal gene splicing; however, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has been observed in the germline of at least one individual with high grade serous ovarian carcinoma (Meisel 2014). BRCA1 c.4986+4A>C was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The adenine (A) nucleotide that is altered is conserved in mammals. Based on the currently available information, we consider BRCA1 c.4986+4A>C to be a likely pathogenic variant.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480773	SCV000605897	likely pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing	The BRCA1 c.4986+4A>C variant has been reported in the published literature in a patient with serous ovarian cancer and associated with an abnormal immunohistochemistry result for BRCA1 (PMID: 21523855 (2011) and 25281711 (2014)). Additionally, functional evidence suggests that this variant may impact BRCA1 protein function (PMID: 30209399 (2018)). Two other variants affecting the same nucleotide, c.4986+4A>T and c.4986+4A>G, have been reported in individuals with breast and/or ovarian cancer, and shown experimentally to cause aberrant splicing (PMID: 21203900 (2011) and 23239986 (2012)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper BRCA1 mRNA splicing. Based on the available information, this variant is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496440	SCV000636003	pathogenic	Hereditary breast ovarian cancer syndrome	2024-08-04	criteria provided, single submitter	clinical testing	This sequence change falls in intron 15 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 25281711, 29446198). This variant is also known as IVS16+4A>C. ClinVar contains an entry for this variant (Variation ID: 37619). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 30209399). This variant disrupts the 4986+4A nucleotide in the BRCA1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 21203900, 23239986, 30209399). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000570191	SCV000660951	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-25	criteria provided, single submitter	clinical testing	The c.4986+4A>C intronic pathogenic mutation results from an A to C substitution 4 nucleotides after coding exon 14 in the BRCA1 gene. This alteration has previously been detected in an individual diagnosed with ovarian cancer, and tumor analysis showed abnormal (loss) BRCA1 IHC results (Meisel JL et al, Ann. Oncol. 2014 Dec; 25(12):2372-8). This alteration has also been identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). 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). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies on this alteration and a different nucleotide change at that same position (c.4986+4A>G) resulted in an alternate transcript with insertion of 65 intronic nucleotides, resulting in a premature termination codon (Ambry internal data; Wappenschmidt B et al. PLoS ONE 2012; 7(12):e50800). In addition, a different nucleotide change at the same position (c.4986+4A>T) was reported as a pathogenic intronic splicing mutation in a cohort of 585 Slovak individuals with family histories of breast and ovarian cancer (Konecny M et al, Breast Cancer Res. Treat. 2011 Feb; 126(1):119-30). Of note, this alteration is also designated as IVS16+4A>C in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496440	SCV000699188	pathogenic	Hereditary breast ovarian cancer syndrome	2016-09-28	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.4986+4A>C variant involves the alteration of a highly conserved intronic nucleotide. Mutation Taster predicts a damaging outcome for this variant. 4/4 splice prediction tools predict a significant impact on normal splicing. This variant is absent in 121392 control chromosomes from ExAC. This variant is reported in at least four HBOC patients in literature and/or clinical databases. In one case, immunohistochemistry revealed a loss of BRCA1 protein, supporting that the variant has a functional effect on protein expression (Meisel_2014). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. This intronic nucleotide position is clinically important as A>T change the same position is pathogenic. In addition, a nearby intronic variant, c.4986+6T>C, is a known pathogenic/likely pathogenic variant. Taken together, the variant of interest is classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000570191	SCV001359061	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-02-06	criteria provided, single submitter	clinical testing	This variant causes an A>C nucleotide substitution at the +4 position of intron 15 of the BRCA1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Another variant at this position results in the use of a cryptic donor at +65 bases as determined by RT-PCR of carrier RNA that is predicted to create a premature translation termination (PMID 23239986). This variant has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in an individual affected with ovarian cancer (PMID: 25281711) and individuals reported in breast and ovarian cancer databases, UMD and BIC (PMID: 21523855, 22144684, http://www.umd.be/BRCA1/4DACTION/WV/7898*/TUdLXOQBPkHswis). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000031200	SCV000053800	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2013-03-19	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031200	SCV000145234	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496440	SCV000587441	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000031200	SCV001243314	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro