ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2492G>A (p.Arg831Lys) (rs771382903)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000549959 SCV000633615 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-07-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 831 of the BRIP1 protein (p.Arg831Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant also falls at the last nucleotide of exon 17 of the BRIP1 coding sequence, which is part of the consensus splice site for this exon. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). This variant is present in population databases (rs771382903, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRIP1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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