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

dbSNP: rs80358108

Total submissions: 3

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	RCV000258202	SCV000326387	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496218	SCV000758887	pathogenic	Hereditary breast ovarian cancer syndrome	2021-05-19	criteria provided, single submitter	clinical testing	This variant, also known as IVS10-2A>T, has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 267618). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 9 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Experimental studies have shown that different variants affecting this nucleotide (c.671-2A>C and c.671-2A>G) disrupt normal splicing and result in aberrant transcripts with one or more exons missing (PMID: 14513821, 24212087). BRCA1 c.671-2A>C is also called IVS10-2A>C in the literature. This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584).
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496218	SCV000587068	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research