Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5074+2T>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 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, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43067606-A-G is Pathogenic according to our data. Variant chr17-43067606-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 37631.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43067606-A-G is described in Lovd as [Pathogenic]. Variant chr17-43067606-A-G is described in Lovd as [Likely_pathogenic]. Variant chr17-43067606-A-G is described in Lovd as [Pathogenic].
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 = 0.999563 -
Jul 01, 2015
Department of Medical Genetics, Oslo University Hospital
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
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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Mar 31, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant causes a T to C nucleotide substitution at the +2 position of intron 16 of the BRCA1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. A study using peripheral blood-derived RNA from a carrier has shown that this variant impacts normal RNA splicing (PMID: 30159786). A viability assay using human haploid cell line has shown that this variant disrupts normal BRCA1 function (PMID: 30209399). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 25556971, 27914478, 29339979, 30159786, Color internal data). In addition, a multifactorial likelihood model using health history and tumor pathology data have suggested this variant have a high probability of being pathogenic (PMID: 31131967). 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. -
Jan 21, 2025
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.5074+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 15 in the BRCA1 gene. This alteration has been previously reported in numerous patients undergoing genetic testing based on personal and/or family history concerning for hereditary breast and ovarian cancer (HBOC) syndrome (Lourenco J et al. Genet Mol Biol. Sao Paulo. 2004;27(4):500-504; Trujillano D et al. J Mol Diagn. 2015 Mar;17:162-70; Maistro S et al. BMC Cancer, 2016 Dec;16:934; Chen L et al. Breast Cancer Res Treat, 2020 Apr;180:759-766). 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 Oct;562:217-222). This alteration was also classified as pathogenic in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence and tumor pathology and case-control data (Parsons MT et al. Hum Mutat, 2019 Sep;40:1557-1578). 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
Jan 31, 2014
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research
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Nov 05, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change affects a donor splice site in intron 16 of the BRCA1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). 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: 25556971, 27914478, 28717669, 29339979, 29446198). This variant is also known as IVS17+2T>C. ClinVar contains an entry for this variant (Variation ID: 37631). 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: 31131967). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 30209399). For these reasons, this variant has been classified as Pathogenic. -
Malignant tumor of breast Pathogenic:1
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Department of Pathology and Laboratory Medicine, Sinai Health System