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

dbSNP: rs80358108

Total submissions: 6

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	RCV000112767	SCV000326385	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000112767	SCV000576446	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-02-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000565769	SCV000660956	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-11	criteria provided, single submitter	clinical testing	The c.671-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 9 in the BRCA1 gene. This mutation was reported in a high-risk breast cancer family and was shown to result in an aberrant RNA splicing transcript without coding exon 9 (Exon 11 in the literature, Keaton JC et al. J. Hum. Genet. 2003 ; 48(8):399-403). 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 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.
Color Diagnostics, LLC DBA Color Health	RCV000565769	SCV000911277	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-04-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853029	SCV002296559	likely pathogenic	Hereditary breast ovarian cancer syndrome	2022-03-10	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. 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: 29446198, 29470806). ClinVar contains an entry for this variant (Variation ID: 55663). Studies have shown that disruption of this splice site results in multiple aberrant transcripts that delete exon 10 (referred to as exon 11) (PMID: 14513821). 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.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112767	SCV000145659	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1999-06-21	no assertion criteria provided	clinical testing