Submissions for variant NM_032043.3(BRIP1):c.1340+2_1340+5del

dbSNP: rs2077945546

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001176004	SCV001339817	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-09-30	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides from +2 to +5 position in intron 9 of the BRIP1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRIP1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae	RCV001875795	SCV002111205	likely pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2021-04-23	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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 variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 918431). This sequence change affects a splice site in intron 9 of the BRIP1 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 BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575).
Ambry Genetics	RCV001176004	SCV002693643	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-09-28	criteria provided, single submitter	clinical testing	The c.1340+2_1340+5delTAAG intronic variant, located in intron 8 of the BRIP1 gene, results from a deletion of 4 nucleotides within intron 8 and involves the canonical splice donor site after coding exon 8 of the BRIP1 gene. In silico splice site analysis predicts that this alteration will weaken the native splice donor 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. As such, this alteration is classified as likely pathogenic.
Myriad Genetics, Inc.	RCV003336311	SCV004045295	likely pathogenic	Familial cancer of breast	2023-06-01	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.