ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1340+5G>C (rs869312791)

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Total submissions: 4
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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 2019-12-26 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 nucleotide position is highly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; 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 Health, Inc RCV000210143 SCV000909783 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-10 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causes intron 9 retention or exon 9 skipping, creating a premature translation stop signal in the RNA transcripts (unpublished targeted RNAseq data from the King Lab, 2017 ASHG cBROCA abstract 796W at https://www.ashg.org/wp-content/uploads/2019/10/2017-Poster-Abstracts.pdf).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, and Color 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.
Invitae RCV001070293 SCV001235515 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2020-03-08 criteria provided, single submitter clinical testing 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, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with ovarian cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 224563). 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. 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.

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