Submissions for variant NM_032043.3(BRIP1):c.1474-1G>A

dbSNP: rs1555603638

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000569916	SCV000666198	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-11-05	criteria provided, single submitter	clinical testing	The c.1474-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 10 of the BRIP1 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; 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.
Counsyl	RCV000662723	SCV000785483	likely pathogenic	Fanconi anemia complementation group J; Ovarian neoplasm	2017-08-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758988	SCV000887981	likely pathogenic	not provided	2024-10-17	criteria provided, single submitter	clinical testing	The BRIP1 c.1474-1G>A variant disrupts a canonical splice-acceptor site and is predicted to interfere with normal BRIP1 mRNA splicing. This variant has not been reported in individuals with BRIP1-related conditions in the published literature. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780062	SCV000917084	likely pathogenic	Familial cancer of breast	2018-09-07	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.1474-1G>A 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: Three predict the variant abolishes a 5' splicing donor site and also introduces a cryptic 5' donor site 1bp into the exon, which is predicted to lead to a frameshift and truncated or absent protein. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 246022 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1474-1G>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001867860	SCV002256269	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2024-05-02	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 10 of the BRIP1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 481627). Studies have shown that disruption of this splice site results in skipping of exon 11 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000780062	SCV004019308	likely pathogenic	Familial cancer of breast	2023-02-27	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.
Baylor Genetics	RCV000780062	SCV004211336	likely pathogenic	Familial cancer of breast	2022-07-31	criteria provided, single submitter	clinical testing