Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.134+3A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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 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 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43115723-T-G is Pathogenic according to our data. Variant chr17-43115723-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 54212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43115723-T-G is described in Lovd as [Pathogenic].
The c.134+3A>C intronic pathogenic mutation results from an A to C substitution 3 nucleotides after coding exon 2 in the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This alteration has been detected in multiple HBOC families (Phelan CM et al. Hum Mutat, 2002 Nov;20:352-7; Claes K et al. Genes Chromosomes Cancer, 2003 Jul;37:314-20). RNA analyses have demonstrated that this alteration leads to skipping of exon 3 (coding exon 2), thereby deleting 18 amino acids from the highly conserved RING domain (Claes K et al. Genes Chromosomes Cancer, 2003 Jul;37:314-20; Steffensen AY et al. Eur J Hum Genet, 2014 Dec;22:1362-8). 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). Of note, this alteration is also referred to as IVS3+3A>C in the literature. Another alteration impacting the same donor site (c.134+3A>T) has been shown to have the same deleterious splicing impact as the c.134+3A>C alteration (Ambry internal data; Baert A et al. Hum. Mutat., 2018 04;39:515-526). 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. -
Pathogenic, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Oct 07, 2019
This variant causes an A>C nucleotide substitution at the +3 position of intron 3 of the BRCA1 gene. Functional RNA studies and mini-gene assay have shown that this variant causes in-frame skipping of exon 3 (PMID: 12759930, 24667779), resulting in loss of the RING domain which is important for BARD1 binding. This variant has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 12402332, 12759930, 24667779). 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. Based on the available evidence, this variant is classified as Pathogenic. -
not provided Pathogenic:1
Pathogenic, no assertion criteria provided
clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
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Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Jun 13, 2022
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the RING domain of the BRCA1 protein, which mediates BRCA1 interactions with BARD1 and BAP1 and is important for ubiquitin ligase activity (PMID: 20029420, 25652403). While functional studies have not been performed to directly test the effect of this variant on BRCA1 protein function, this suggests that disruption of this region of the protein is causative of disease. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 12759930, 24667779). Experimental studies have shown that this variant affects BRCA1 function (PMID: 30209399). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 54212). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12402332, 12759930, 32341426). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 3 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. -