Submissions for variant NM_032043.3(BRIP1):c.1340+5G>C

dbSNP: rs869312791

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210143	SCV000266159	uncertain significance	Hereditary cancer-predisposing syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000210143	SCV000664824	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-12	criteria provided, single submitter	clinical testing	The c.1340+5G>C intronic variant results from a G to C substitution 5 nucleotides after coding exon 8 in the BRIP1 gene. This alteration has been detected in an individual diagnoses with ovarian cancer (Shirts BH et al. Genet Med, 2016 10;18:974-81). This nucleotide position is highly conserved in available vertebrate species. 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). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000210143	SCV000909783	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the +5 position of intron 9 of the BRIP1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies have shown that this variant allele causes intron 9 retention or exon 9 skipping, creating a premature translation stop signal in the RNA transcripts (unpublished targeted RNAseq data from the King Lab, 2017 ASHG cBROCA abstract 796W at https://www.ashg.org/wp-content/uploads/2019/10/2017-Poster-Abstracts.pdf). The aberrant transcripts are expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with ovarian cancer (PMID: 26845104; Color Health internal data). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001070293	SCV001235515	likely pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2023-08-14	criteria provided, single submitter	clinical testing	Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 9 as well as activation of cryptic splice sites and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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 falls in intron 9 of the BRIP1 gene. It does not directly change the encoded amino acid sequence of the BRIP1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. ClinVar contains an entry for this variant (Variation ID: 224563). This variant has been observed in individual(s) with ovarian cancer (PMID: 26845104). This variant is not present in population databases (gnomAD no frequency).
Baylor Genetics	RCV003474990	SCV004211346	uncertain significance	Familial cancer of breast	2022-05-13	criteria provided, single submitter	clinical testing