Submissions for variant NM_007294.4(BRCA1):c.671-1G>C

dbSNP: rs80358020

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236539	SCV000293326	uncertain significance	not provided	2024-11-05	criteria provided, single submitter	clinical testing	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)
Ambry Genetics	RCV002362721	SCV002666750	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-12-07	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003644898	SCV004429494	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-01-02	criteria provided, single submitter	clinical testing	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). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 35220195). 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).
All of Us Research Program, National Institutes of Health	RCV000077180	SCV004839092	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-01-08	criteria provided, single submitter	clinical testing	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.
Sharing Clinical Reports Project (SCRP)	RCV000077180	SCV000108977	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2012-08-31	flagged submission	clinical testing