Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The ENST00000357654.9(BRCA1):c.670+1del variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
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 4 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 9, offset of 0 (no position change), new splice context is: aagGTaatg. 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;
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Jan 24, 2018
The c.670+1delG intronic variant, located in intron 8 of the BRCA1 gene, results from a deletion of one nucleotide within intron 8 of the BRCA1 gene. 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 at a splice junction that is located at a naturally occurring, alternatively spliced exon and, thus, the degree and effects of abnormal splicing cannot be predicted (Colombo M et al. Hum. Mol. Genet., 2014 Jul;23:3666-80). This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is expected to shift the native splice donor site upstream by one nucleotide. This prediction is supported by the literature which shows by mini-gene that splicing occurs one nucleotide into the foregoing exon (Steffensen AY et al. Eur. J. Hum. Genet., 2014 Dec;22:1362-8). 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
Mar 03, 2018
This sequence change affects a donor splice site in intron 9 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 267611). Experimental studies have shown that this change results in the generation of an aberrant transcript that leads to the in-frame activation of a cryptic donor splice site in exon 9, located 1 nucleotide upstream of the natural splice site (PMID: 24667779). However, an in-frame BRCA1 isoform that skips exons 8 and 9 (also known as exons 9 and 10) is naturally expressed in normal blood and breast tissue, suggesting that this splice donor variant may not be deleterious (PMID: 24569164). 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. -