Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5467+2T>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000657 in 152,212 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely 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, Cryptic splice site detected, with MaxEntScore 5.4, offset of 5, new splice context is: aagGTgcct. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43047641-A-G is Pathogenic according to our data. Variant chr17-43047641-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 125851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43047641-A-G is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2Other:1
Oct 02, 2015
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Breast Cancer Information Core (BIC) (BRCA1)
Significance: Pathogenic
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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Hereditary breast ovarian cancer syndrome Pathogenic:2
Mar 14, 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 22 of the BRCA1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs80358009, gnomAD 0.007%). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 18694767, 29446198). ClinVar contains an entry for this variant (Variation ID: 125851). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the BRCA1 protein in which other variant(s) (p.Tyr1853*) have been determined to be pathogenic (PMID: 7894493, 10811118, 11739404, 12400015, 20104584, 21922593, 24504028). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Mar 24, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: The c.5467+2T>C in a BRCA1 gene is a splice-site variant that alters a conserved nucleotide. 5/5 in silico tools via Alamut predict this variant to disrupt a canonical donor sequence, however these predictions have yet to be confirmed by functional assay. The variant is absent from ExAC and been reported in affected individual(s) via publications and/or reputable database/clinical laboratory as Likely Pathogenic. Taken together, the variant was classified as Likely Pathogenic until additional information becomes available. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.5467+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 21 in the BRCA1 gene. This alteration occurs at the 3' terminus of the BRCA1 gene and is not expected to trigger nonsense-mediated mRNA decay. The exact functional effect of this alteration is unknown; however, the impacted BRCT2 domain is critical for protein function (Ambry internal data). This mutation has been reported in several unrelated families suspected of having hereditary breast and ovarian cancer (HBOC) syndrome (Tommasi S et al. Mutat. Res., 2008 Sep;644:64-70; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. One in vitro RNA study demonstrated that this variant resulted in skipping of coding exon 21 (designated as exon 23) (Leman R et al. Nucleic Acids Res, 2018 09;46:7913-7923). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -