Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_007294.4(BRCA1):c.4986+1G>T variant causes a splice donor 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]
Verdict is Pathogenic. Variant got 22 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
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 17-43070927-C-A is Pathogenic according to our data. Variant chr17-43070927-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 37618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43070927-C-A is described in Lovd as [Pathogenic]. Variant chr17-43070927-C-A is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter
clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Oct 02, 2015
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Pathogenic, criteria provided, single submitter
clinical testing
Department of Medical Genetics, Oslo University Hospital
Jul 01, 2015
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Pathogenic, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
Jan 22, 2010
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not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
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not provided Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Nov 11, 2022
This variant disrupts a canonical splice-donor site and interferes with normal BRCA1 mRNA splicing. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with hereditary breast and/or ovarian cancer (PMIDs: 22798144 (2012), 28176296 (2017), and 30702160 (2019)), as well as individuals with an increased risk for breast and/or ovarian cancer (PMIDs: 29339979 (2018) and 29446198 (2018)). Studies on the variant's splicing impact show the loss of a natural donor site with only partial retention of intron 16 compared to typical BRCA1 splicing (PMID: 23451180 (2013)). Based on the available information, this variant is classified as pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Invitae
Jan 16, 2022
ClinVar contains an entry for this variant (Variation ID: 37618). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in partial inclusion of intron 15 and introduces a premature termination codon (PMID: 23451180). The resulting mRNA is expected to undergo nonsense-mediated decay. Experimental studies have shown that disruption of this splice site 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. Disruption of this splice site has been observed in individual(s) with or undergoing testing for hereditary breast and/or ovarian cancer (PMID: 22798144, 28176296, 29339979, 29446198). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 15 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. -