Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5
The ENST00000357654.9(BRCA1):c.594-2A>G variant causes a splice acceptor change. The variant allele was found at a frequency of 0.000000686 in 1,457,768 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 Conflicting classifications of pathogenicity (no stars).
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 Uncertain_significance. Variant got 5 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.013590844 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.7, offset of -21, new splice context is: taactagtgtttcttattAGgac. Cryptic site results in inframe 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 17-43095924-T-C is Pathogenic according to our data. Variant chr17-43095924-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55644.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=2, not_provided=1}. Variant chr17-43095924-T-C is described in Lovd as [Pathogenic].
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Dec 20, 2023
The c.594-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 8 in the BRCA1 gene. This variant has been reported in one family from a Dutch hereditary breast and ovarian cancer cohort (van der Hout AH et al. Hum Mutat, 2006 Jul;27:654-66). This alteration has also been detected in 1/2575 unselected patients with breast cancer from a Malaysian cohort (Wen WX et al. J Med Genet, 2018 Feb;55:97-103). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). 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. However, this alteration occurs in one of the exons that is absent in a predominant, in-frame, naturally occurring isoform (Δ7_8, also known as Δ9,10 in the literature) and is likely to be spliced out in this normal isoform that produces a partially functional protein (Colombo M et al. Hum. Mol. Genet. 2014 Jul;23:3666-80; Whiley PJ et al. Clin.Chem. 2014 Feb;60:341-52). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Nov 06, 2019
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that variant(s) at this splice acceptor site (c.594-2A>C) result in the generation of two aberrant transcripts, one that leads to out-of-frame skipping of exon 9 (denoted as del10), and one that leads to the in-frame activation of a cryptic acceptor splice site located 21 nucleotides upstream of the natural splice site in intron 8 (ins21) (PMID: 23239986, 24212087, 24667779). However, an in-frame BRCA1 isoform that skips exons 8 and 9 (also known as exons 9 and 10) is expressed in normal blood and breast tissue, suggesting that this isoform may not be deleterious (PMID: 24569164). This variant has been observed in individuals affected with breast and/or ovarian cancer (PMID: 16683254, 28993434). ClinVar contains an entry for this variant (Variation ID: 55644). This variant is present in population databases (rs80358033, ExAC 0.002%). This sequence change affects an acceptor splice site in intron 8 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -
Familial cancer of breast Other:1
not provided, no classification provided
literature only
ClinVar Staff, National Center for Biotechnology Information (NCBI)