Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5152+1G>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as 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]
BRCA1 Gene-Disease associations (from GenCC):
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Our verdict: Pathogenic. The variant received 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.013948498 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43063873-C-G is Pathogenic according to our data. Variant chr17-43063873-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 37642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
This variant causes a G to C nucleotide substitution at the +1 position of intron 17 of the BRCA1 gene. An RNA study has shown in two unrelated variant carriers that this variant causes in-frame skipping of exon 17, resulting in loss of functionally important residues in the BRCT domain (PMID: 23239986). A functional study has reported that this variant impacts BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been observed in multiple individuals affected with breast and ovarian cancer (PMID: 9760198, 22798144, 23239986, 26845104). 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. -
Apr 22, 2025
Ambry Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The c.5152+1G>C intronic pathogenic mutation (also known as IVS18+1G>C in the literature) results from a G to C substitution one nucleotide after coding exon 16 of the BRCA1 gene. This alteration has been reported in multiple individuals with personal and/or family histories consistent with hereditary breast and ovarian cancer syndrome (Examples- Dong J et al. Hum. Genet., 1998 Aug;103:154-61; Seong MW et al. Clin. Genet., 2009 Aug;76:152-60; Kim H et al. Breast Cancer Res. Treat., 2012 Aug;134:1315-26; Rebbeck TR et al. Hum. Mutat., 2018 May;39:593-620). A 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 nucleotide position is highly conserved in available vertebrate species. 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. RNA studies have demonstrated that this alteration results in skipping of CDS16 in the set of samples tested (Wappenschmidt B et al. PLoS One, 2012 Dec;7:e50800). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Hereditary breast ovarian cancer syndromePathogenic:2
Mar 12, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change affects a donor splice site in intron 17 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. 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 and/or ovarian cancer (PMID: 9760198, 19656164, 23239986, 25863477, 26845104). This variant is also known as IVS18+1G>C. ClinVar contains an entry for this variant (Variation ID: 37642). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects BRCA1 function (PMID: 30209399). 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: 23239986; Invitae). This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Ser1715Asn) have been determined to be pathogenic (PMID: 11157798, 20516115, 28781887, 30209399, 30765603; 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. For these reasons, this variant has been classified as Pathogenic. -
Nov 22, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Variant summary: BRCA1 c.5152+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251212 control chromosomes (gnomAD). c.5152+1G>C has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Dong_1998, Wappenschmidt_2012, Kang_2015, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
BRCA1-related disorderPathogenic:1
Jul 25, 2024
PreventionGenetics, part of Exact Sciences
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
The BRCA1 c.5152+1G>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in several individuals with a personal or family history of breast or ovarian cancer (see, for example, Dong et al. 1998. PubMed ID: 9760198; Kim et al. 2012. PubMed ID: 22798144; Rebbeck et al. 2018. PubMed ID: 29446198; Abulkhair et al. 2018. PubMed ID: 30199306). It has also been reported in an individual with colorectal cancer (Table S3, AlHarbi et al. 2023. PubMed ID: 37306523). RT_PCR studies suggest this variant impacts mRNA splicing (Wappenschmidt et al. 2012. PubMed ID: 23239986), and in vitro analysis suggested this variant renders the gene non-functional (Findlay et al. 2018. PubMed ID: 30209399). This variant has not been reported in a large population database, indicating it is rare in the general population. In ClinVar, this variant classified as pathogenic by several submitters (https://www.ncbi.nlm.nih.gov/clinvar/variation/37642/). Variants that disrupt the consensus splice donor site in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic. -