Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_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 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
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
Pathogenic, reviewed by expert panel
curation
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Jun 18, 2019
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 -
Pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
Nov 10, 2022
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not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
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Uncertain significance, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Jun 20, 2002
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not provided Pathogenic:2
Pathogenic, no assertion criteria provided
clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
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Pathogenic, no assertion criteria provided
clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
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
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Oct 21, 2022
For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in aberrant mRNA splicing and introduces a premature termination codon (PMID: 20614180, 23893897, 30209399). The resulting mRNA is expected to undergo nonsense-mediated decay. Experimental studies have shown that this variant affects BRCA1 function (PMID: 30209399). 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). ClinVar contains an entry for this variant (Variation ID: 55719). This variant is also known as IVS2-9C>G. This variant has been observed in individual(s) with breast cancer (PMID: 18704682). This variant is present in population databases (rs80358127, gnomAD 0.006%). 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 disrupted protein product. -