Submissions for variant NM_032043.3(BRIP1):c.2905+3A>G

gnomAD frequency: 0.00001  dbSNP: rs1555573247

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000570919	SCV000666181	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-02	criteria provided, single submitter	clinical testing	The c.2905+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 18 in the BRIP1 gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001210391	SCV001381876	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-09-13	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. Variants that disrupt 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. ClinVar contains an entry for this variant (Variation ID: 481619). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 19 of the BRIP1 gene. It does not directly change the encoded amino acid sequence of the BRIP1 protein. It affects a nucleotide within the consensus splice site.
Color Diagnostics, LLC DBA Color Health	RCV000570919	SCV002052388	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-08	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the +3 position of intron 19 of the BRIP1 gene. Splice site prediction tools suggest that this variant may impact RNA splicing, although this prediction has not been confirmed in published RNA studies. 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). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV003476330	SCV004211337	uncertain significance	Familial cancer of breast	2022-07-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478233	SCV004220713	uncertain significance	not provided	2023-06-29	criteria provided, single submitter	clinical testing	This variant has not been reported in the published literature. It also has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper BRIP1 mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant.