Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_007294.4(BRCA1):c.671-1G>C variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. 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 Likely_pathogenic. Variant got 7 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.61248213 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43094861-C-G is Pathogenic according to our data. Variant chr17-43094861-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 91663.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=3}.
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Jan 08, 2024
This variant causes a G to C nucleotide substitution at the -1 position of intron 9 of the BRCA1 gene. This variant is also known as IVS10-1G>C based on Breast Cancer Information Core (BIC) nomenclature. RNA studies on total RNA from carriers of BRCA1 c.671-2A>C and c.671-2A>G have reported the skipping of exon 10 and exons 8-10 that result in in-frame deletion and the out-of-frame skipping of exons 9 and 10 (PMID: 14513821, 24212087, 29774201, 30736279). Functional studies have reported that the skipping of exon 10, while reduces some BRCA1 function, does not completely abolish its activity for DNA damage repair and cell proliferation (PMID: 8972225, 11359908, 16949048). Collectively, the RNA and functional studies suggest that canonical splice site variants at intron 9 acceptor site may retain some BRCA1 activity similar to a leaky splice variant. This variant has been reported in an individual affected with breast cancer (PMID: 35220195). Other canonical splice site variants at the intron 9 splice acceptor site have been reported in 6 individuals affected with breast and/or ovarian cancer (PMID: 26911350, 28145423, 35918668) and multiple suspected breast and ovarian cancer families (PMID: 12960223, 29446198, 32614418) and individuals affected with lung cancer and melanoma (PMID: 33610559, 35712480). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter
clinical testing
Ambry Genetics
Dec 07, 2021
The c.671-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 9 of the BRCA1 gene. 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. 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 exon, which comprises over 50% of the BRCA1 protein, is absent in part or in whole in naturally occurring alternative splicing isoforms (Colombo M et al. Hum Mol Genet 2014 Jul;23(14):3666-80). Functional studies have shown that loss of this exon may impair cellular localization and have reduced, but not lost, DNA damage repair function (Thakur S et al. Mol Cell Biol 1997 Jan;17(1):444-52, Huber LJ et al. Mol Cell Biol 2001 Jun;21(12):4005-15, Kim SS et al. Mol Cell Biol 2006 Sep;26(18):6983-92). Additionally, mouse embryos with homozygous BRCA1 coding exon 9 deletions survive longer than BRCA1-null embryos, suggesting protein without exon 9 may still be able to perform some BRCA1 essential functions (Huber LJ et al. Mol Cell Biol 2001 Jun;21(12):4005-15). Based on the majority of available evidence to date, this variant is likely pathogenic. However, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA1 alteration. As risk estimates are unknown at this time, clinical correlation is advised. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Jan 02, 2023
Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 35220195). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 91663). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 9 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). -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Nov 05, 2024
Canonical splice site variant resulting in multiple different transcripts, including full-length, in-frame deletion of exon 10, also known as exon 11 by alternate numbering, and various out-of-frame isoforms (PMID: 24212087, 30736279, 29774201); Observed in an individual with breast cancer (PMID: 35220195); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 790-1G>C; This variant is associated with the following publications: (PMID: 35220195, 38219492) -