Submissions for variant NM_007294.4(BRCA1):c.671-2A>G

dbSNP: rs80358108

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000258427	SCV000326386	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000823108	SCV000699287	likely pathogenic	Hereditary breast ovarian cancer syndrome	2019-11-21	criteria provided, single submitter	clinical testing	Variant Summary: BRCA1 c.671-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. Several publications report experimental evidence that this variant affects mRNA splicing with the most recent one confirming this observation utilizing RNA in situ hybridization to measure the absolute expression of BRCA1 mRNA splicing events in single lymphoblastoid cells containing this variant (Whiley_2014, Lattimore_2018, and Lattimore_2019). The variant was absent in 236750 control chromosomes. c.671-2A>G has been reported in at-least one individual the literature in a sequencing study of Australian women affected with Ovarian Cancer (Alsop_2012). This patient is also cited in the kConfab and Leiden Open Source variation databases and immortalized lymphoblastoid cell lines derived from this carrier were utilized in subsequent studies. In the absence of co-segregation studies, these report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic using overlapping evidences utilized in the context of this evaluation. Based on the evidence outlined above, until additional clinical cases of patients and families with this variant are reported, it was re-classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000823108	SCV000963952	pathogenic	Hereditary breast ovarian cancer syndrome	2024-04-25	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 personal and/or family history of breast and/or ovarian cancer (PMID: 22711857, 26689913, 29446198). ClinVar contains an entry for this variant (Variation ID: 267617). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 24212087). This variant disrupts the nuclear localization signal, DNA binding domain and coiled-coil domain of BRCA1, which mediate interactions with RAD51, RAD50 and PALB2 (PMID: 25652403, 22737296). While functional studies have not been performed to directly test the effect of this variant on BRCA1 protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001572199	SCV001796799	uncertain significance	not provided	2020-08-05	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 (Whiley 2014, Lattimore 2018, Lattimore 2019); Observed in individuals with ovarian cancer (Alsop 2012); Not observed in large population cohorts (Lek 2016); Also known as 790-2A>G or IVS10-2A>G; This variant is associated with the following publications: (PMID: 29774201, 20167696, 22711857, 30736279, 31131967, 24212087, 29446198)
Ambry Genetics	RCV002365286	SCV002665968	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-04-02	criteria provided, single submitter	clinical testing	The c.671-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 9 in 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.