Submissions for variant NM_032043.3(BRIP1):c.206-1G>T

dbSNP: rs1555617934

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000563712	SCV000668959	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-17	criteria provided, single submitter	clinical testing	The c.206-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 3 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 and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in low level abnormal splicing and introduces a small in-frame deletion in the set of samples tested, however, functional impact is unclear at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000693188	SCV000821047	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 3 of the BRIP1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in two alternative in-frame transcripts. These alternative transcripts, one with a loss of 3 amino acid residues and the other with a loss of 4 amino acid residues, are expected to preserve the integrity of the reading-frame and as such, their functional consequence cannot be determined. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with ovarian cancer (PMID: 26720728). ClinVar contains an entry for this variant (Variation ID: 483196). Studies have shown that disruption of this splice site results in the activation of two different cryptic splice sites in exon 4, but the impact on the resulting protein products is unknown (Invitae). 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.
GeneDx	RCV001755942	SCV002006904	uncertain significance	not provided	2024-06-17	criteria provided, single submitter	clinical testing	A different variant affecting the same splice site (c.206-2A>G) has been demonstrated to result in abnormal splicing; however, the effect on protein function is unknown (External communication with Ambry Genetics and Invitae); Canonical splice site variant with an unclear effect on protein function; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Color Diagnostics, LLC DBA Color Health	RCV000563712	SCV004360304	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the -1 position of intron 3 of the BRIP1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. An RNA study at an external laboratory has shown that this variant results in transcripts with an in-frame deletion of 3 or 4 amino acids (ClinVar SCV000668959.5). Functional consequence of these alternate transcripts is not clear. To our knowledge, 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). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance.