Submissions for variant NM_032043.3(BRIP1):c.2492+5G>C

dbSNP: rs763222019

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218546	SCV000275935	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-22	criteria provided, single submitter	clinical testing	The c.2492+5G>C intronic variant results from a G to C substitution 5 nucleotides after coding exon 16 in 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 donor site and may result in the creation or strengthening of a novel splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000485890	SCV000572041	uncertain significance	not provided	2016-10-17	criteria provided, single submitter	clinical testing	This variant is denoted BRIP1 c.2492+5G>C or IVS17+5G>C and consists of a G>C nucleotide substitution at the +5 position of intron 17 of the BRIP1 gene. Multiple in silico models predict that this variant may damage the natural splice donor site of intron 17 and lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 c.2492+5G>C was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The guanine (G) nucleotide that is altered is conserved across species. Based on currently available evidence, it is unclear whether BRIP1 c.2492+5G>C is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000796530	SCV000936048	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2018-12-06	criteria provided, single submitter	clinical testing	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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. This variant has not been reported in the literature in individuals with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 231934). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 17 of the BRIP1 gene. It does not directly change the encoded amino acid sequence of the BRIP1 protein, but it affects a nucleotide within the consensus splice site of the intron.