Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_007294.4(BRCA1):c.5075-1G>T variant causes a splice acceptor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 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 16 ACMG points.
PVS1
?
PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.013769671 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.4, offset of 42, new splice context is: gacactgaaatattttctAGgaa. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP3
?
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-43063952-C-A is Pathogenic according to our data. Variant chr17-43063952-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43063952-C-A is described in Lovd as [Pathogenic]. Variant chr17-43063952-C-A is described in Lovd as [Pathogenic].
Likely pathogenic, criteria provided, single submitter
clinical testing
Ambry Genetics
Dec 06, 2017
The c.5075-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 17 of the BRCA1 gene. This alteration (designated as IVS17-1G>T) was identified in a Chinese individual diagnosed with breast cancer at 26 who also had a first-degree relative diagnosed with breast cancer (Li WF et al. Breast Cancer Res. Treat., 2008 Jul;110:99-109). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. 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 likely pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Invitae
Jan 30, 2019
For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). Experimental studies have shown that this variant disrupts mRNA splicing and/or protein function (PMID: 30209399). This variant has been observed in an individual affected with breast cancer (PMID: 16456781). This variant is also known as IVS17-1G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 55378). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 16 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -
Breast-ovarian cancer, familial, susceptibility to, 1 Other:1
not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
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Familial cancer of breast Other:1
not provided, no classification provided
literature only
ClinVar Staff, National Center for Biotechnology Information (NCBI)