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>A 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-T is Pathogenic according to our data. Variant chr17-43063873-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 125768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:4
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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Apr 28, 2009
Breast Cancer Information Core (BIC) (BRCA1)
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
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Apr 02, 2020
Department of Molecular Diagnostics, Institute of Oncology Ljubljana
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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Mar 09, 2011
Sharing Clinical Reports Project (SCRP)
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
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Hereditary breast ovarian cancer syndromePathogenic:2
Feb 07, 2022
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>A 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: Four 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 261128 control chromosomes (gnomAD, Palmer_2020). c.5152+1G>A has been reported in the literature in individuals affected with Breast And Ovarian Cancer (example: Pal_2015, Singh_2018, Anjum_2014, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function using saturated genome editing in a haploid cell-survival assay: the variant was found with a functional score supporting loss of function (Findlay_2018). Four ClinVar submitters, including one international consortium (CIMBA), have assessed the variant since 2014: all submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Mar 07, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant is not present in population databases (gnomAD no frequency). 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. Disruption of this splice site has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 22438049, 26287763, 29446198, 29470806). ClinVar contains an entry for this variant (Variation ID: 125768). 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. -
The c.5152+1G>A intronic pathogenic mutation (also known as IVS18+1G>A) results from a G to A substitution one nucleotide after coding exon 16 of the BRCA1 gene. This alteration has been previously reported and classified as pathogenic in the ClinVar database by the Sharing Clinical Reports Project (SCRP) (available from www.ncbi.nlm.nih.gov/clinvar/. Accessed 06/24/2015). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP splice site prediction tool, this alteration is predicted to abolish the native donor splice site; however, direct evidence is unavailable. Since alterations that disrupt the canonical splice donor site are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -