Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_007294.4(BRCA1):c.81-9C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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 12 ACMG points.
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 17-43115788-G-C is Pathogenic according to our data. Variant chr17-43115788-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 55719.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43115788-G-C is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2Uncertain:1Other:1
Nov 10, 2022
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Jun 20, 2002
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Brotman Baty Institute, University of Washington
Significance: not provided
Review Status: no classification provided
Collection Method: in vitro
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Jun 18, 2019
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.996447 -
not provided Pathogenic:2
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.81-9C>G intronic pathogenic mutation results from a C to G substitution 9 nucleotides upstream from coding exon 2 in the BRCA1 gene. This nucleotide position is poorly conserved in available vertebrate species, however, thymidine is the only other observed alternate nucleotide. Using the BDGP and ESEfinder splice site prediction tools predicts a weakening in the native splice acceptor site efficiency and the creation of a new alternate splice acceptor site 8 nucleotides upstream from the native. RNA studies have confirmed this cryptic splice site is used resulting in abnormal splicing in the set of samples tested (Ambry internal data; Joosse SA et al. Breast Cancer Res. Treat., 2012 Apr;132:379-89). In addition, this alteration was shown to be functionally deleterious in a high-throughput haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Based on the majority of evidence available to date, this alteration is interpreted as a disease-causing mutation. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Sep 12, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change falls in intron 2 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 may result in an absent or altered protein product. This variant is present in population databases (rs80358127, gnomAD 0.006%). This variant has been observed in individual(s) with breast cancer (PMID: 18704682). This variant is also known as IVS2-9C>G. ClinVar contains an entry for this variant (Variation ID: 55719). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 30415210). Experimental studies have shown that this variant affects BRCA1 function (PMID: 30209399). Studies have shown that this variant results in aberrant mRNA splicing, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 20614180, 23893897, 30209399). For these reasons, this variant has been classified as Pathogenic. -