ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1628+5G>A (rs754929230)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000572734 SCV000668875 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000572734 SCV000684145 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586595 SCV000699671 uncertain significance not provided 2017-01-03 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.1628+5G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 3/5 splice prediction tools predict the weakening of a cannonical splice donor site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1/121200 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000557392 SCV000633564 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-10-01 criteria provided, single submitter clinical testing This sequence change falls in intron 11 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 present in population databases (rs754929230, ExAC 0.002%). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 461078). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, 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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