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

dbSNP: rs80358020

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131864	SCV000186919	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-10-13	criteria provided, single submitter	clinical testing	The c.671-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 9 of the BRCA1 gene. This alteration was identified in an Asian Indian individual diagnosed with breast cancer at age 38, whose sister and grandmother were also diagnosed with breast cancer (Mannan AU et al. J. Hum. Genet. 2016 Jun;61:515-22). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation-positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). This nucleotide position is completely conserved on sequence alignment 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 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112766	SCV000326382	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Invitae	RCV000496515	SCV000940204	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-14	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 29446198, 29470806). ClinVar contains an entry for this variant (Variation ID: 125908). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001580455	SCV001817556	uncertain significance	not provided	2020-08-24	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28726806, 29446198, 29470806, 28152038, 21523855, 12960223, 26911350, 31131967)
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112766	SCV000145658	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496515	SCV000587069	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Center for Precision Medicine, Meizhou People's Hospital	RCV002250562	SCV002520908	likely pathogenic	Familial cancer of breast		no assertion criteria provided	literature only