ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.206-1G>T (rs1555617934)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000563712 SCV000668959 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-22 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. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native 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.
Invitae RCV000693188 SCV000821047 likely pathogenic Familial cancer of breast; Fanconi anemia, complementation group J 2020-09-24 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 3 of the BRIP1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 483196). 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). 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.
Color Health, Inc RCV000563712 SCV001344519 likely pathogenic Hereditary cancer-predisposing syndrome 2020-12-22 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. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. 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). Loss of BRIP1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.

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