Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5278-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000684 in 1,461,502 control chromosomes in the GnomAD database, with no homozygous occurrence. 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]
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 8, offset of 8, new splice context is: ctcttcttccaaatcttcAGggg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43051118-C-T is Pathogenic according to our data. Variant chr17-43051118-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 55500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43051118-C-T is described in Lovd as [Pathogenic]. Variant chr17-43051118-C-T is described in Lovd as [Pathogenic].
Hereditary breast ovarian cancer syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Jan 09, 2024
This sequence change affects an acceptor splice site in intron 19 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted 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 and/or ovarian cancer (PMID: 9333265, 23239986, 26187060, 29446198, 29470806). This variant is also known as IVS20-1G>A. ClinVar contains an entry for this variant (Variation ID: 55500). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 23239986, 30209399). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter
curation
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Jan 08, 2024
PVS1_RNA; PM2_sup;. According to the ClinGen ENIGMA BRCA1 v1.0.0 criteria we chose these criteria: PVS1 (very strong pathogenic): PVS1 (RNA) , PS3 (strong pathogenic): Intronic variant, functional data considered only from assays that measure effect via mRNA and protein. Reported by one calibrated study incorporating mRNA splicing effects to affect protein function similar to pathogenic control variants (PMID:30209399) (PS3 met)., PM2 (supporting pathogenic): not in gnomAD -
Pathogenic, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Sep 16, 2024
Variant summary: BRCA1 c.5278-1G>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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of BRCA1 function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (e.g., Wappenschmidt_2012). The variant was absent in 251146 control chromosomes. c.5278-1G>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e..g, Shattuck-Eidens_1997, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease.At least one functional study reports experimental evidence evaluating an impact on protein function and showed a loss-of-function effect of this variant on homology directed repair (HDR) activity (e.g. Findlay_2018). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. The following publications have been ascertained in the context of this evaluation (PMID: 30209399, 29446198, 9333265, 23239986). ClinVar contains an entry for this variant (Variation ID: 55500). Based on the evidence outlined above, the variant was classified as pathogenic. -
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2Other:1
Pathogenic, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Jun 21, 1999
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Pathogenic, criteria provided, single submitter
clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
The c.5278-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 19 of the BRCA1 gene. This mutation has been detected in multiple breast and/or ovarian cancer families and two independent splicing analyses have demonstrated aberrant splicing (Shattuck-Eidens D et al. JAMA. 1997 Oct 15;278(15):1242-50; Wappenschmidt B et al. PLoS One. 2012;7(12):e50800; Rodriguez-Balada M et al. Cancer Genet. 2016 Nov;209(11):487-492). Of note, this alteration is described as IVS20-1G>A in published literature. 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. As such, this alteration is classified as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Dec 08, 2020
This variant causes a G to A nucleotide substitution at the -1 position of intron 19 of the BRCA1 gene. RNA studies using RT-PCR on carrier-derived RNA have reported partial and complete skipping of exon 20, causing frameshift in the open reading frame (PMID: 23239986, 27886673). A functional study reported this variant as loss-of-function in a human haploid cell proliferation assay (PMID: 30209399). This variant has been reported in multiple individuals and families affected with breast and ovarian cancer (PMID: 9333265, 18092194, 23239986, 26187060, 27886673, 29470806). 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. -