Submissions for variant NM_032043.3(BRIP1):c.379+1G>T

dbSNP: rs1437158047

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001066581	SCV001231596	likely pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2022-07-19	criteria provided, single submitter	clinical testing	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. Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 860301). Disruption of this splice site has been observed in individual(s) with ovarian cancer (PMID: 26315354). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 4 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.
Ambry Genetics	RCV002355086	SCV002623316	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-09	criteria provided, single submitter	clinical testing	The c.379+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 3 of the BRIP1 gene. In one study, this variant was identified in 1/3236 cases of invasive epithelial ovarian cancer and in 0/3431 European controls (Ramus SJ et al. J Natl Cancer Inst, 2015 Nov;107:). Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is insufficient at this time (Ambry internal data). The exact functional effect of the altered amino acid sequence is unknown. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV004720752	SCV005327612	likely pathogenic	not provided	2024-03-20	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individual(s) with ovarian cancer (PMID: 26315354); This variant is associated with the following publications: (PMID: 26315354)