Submissions for variant NM_007294.3(BRCA1):c.5153-3T>C (rs375639469)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165729	SCV000216470	likely benign	Hereditary cancer-predisposing syndrome	2020-02-12	criteria provided, single submitter	clinical testing	In silico models in agreement (benign);RNA Studies
Invitae	RCV000474546	SCV000549402	uncertain significance	Hereditary breast and ovarian cancer syndrome	2020-10-13	criteria provided, single submitter	clinical testing	This sequence change falls in intron 17 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs375639469, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 91639). This variant has been reported to have conflicting or insufficient data to determine the effect on BRCA1 protein function (PMID: 30209399). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588488	SCV000699214	uncertain significance	not provided	2017-01-03	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.5153-3T>C variant involves the alteration of a non-conserved intronic nucleotide, which 5/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts alterations to ESE binding, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/119938, which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA1 variant of 1/1000. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, although multiple clinical diagnostic laboratories classify the variant as "uncertain significance." Therefore, until additional information becomes available (ie, clinical and/or functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
GeneDx	RCV000588488	SCV000730671	likely benign	not provided	2020-08-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30209399, 31131967)
Color Health, Inc	RCV000165729	SCV000912006	uncertain significance	Hereditary cancer-predisposing syndrome	2019-11-18	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077156	SCV000108953	uncertain significance	Breast-ovarian cancer, familial 1	2009-10-13	no assertion criteria provided	clinical testing
Brotman Baty Institute,University of Washington	RCV000077156	SCV001243686	not provided	Breast-ovarian cancer, familial 1		no assertion provided	in vitro