Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_007294.4(BRCA1):c.4986+4A>C variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 17-43070924-T-G is Pathogenic according to our data. Variant chr17-43070924-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43070924-T-G is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3Other:1
Oct 02, 2015
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Brotman Baty Institute, University of Washington
Significance: not provided
Review Status: no classification provided
Collection Method: in vitro
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Mar 19, 2013
Sharing Clinical Reports Project (SCRP)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Feb 20, 2004
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Hereditary breast ovarian cancer syndrome Pathogenic:3
Jan 31, 2014
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research
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Sep 28, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -
Aug 04, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -
not provided Pathogenic:2
Jul 31, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -
Feb 14, 2017
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -
Review Status: criteria provided, single submitter
Collection Method: 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. -
Feb 06, 2020
Color Diagnostics, LLC DBA Color Health
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -