ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3440dup (p.Asn1147fs) (rs753683450)

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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 RCV000561490 SCV000668913 likely pathogenic Hereditary cancer-predisposing syndrome 2016-07-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Structural Evidence,Other data supporting pathogenic classification
Invitae RCV000636076 SCV000757508 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-08-30 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the BRIP1 gene (p.Asn1147Lysfs*2). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 103 amino acids of the BRIP1 protein. This variant is present in population databases (rs753683450, ExAC 0.1%). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 483163). Experimental studies and prediction algorithms are not available for this variant. While this variant affects the TopBP1-binding region (residues 1130-1153) of the BRIP1 protein (PMID: 20159562, 21127055), the functional significance of disrupting only the C-terminal 7 amino acid residues of this region is currently unknown. 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.
GeneDx RCV000657331 SCV000779063 uncertain significance not provided 2018-12-12 criteria provided, single submitter clinical testing This duplication of one nucleotide in BRIP1 is denoted c.3440dupA at the cDNA level and p.Asn1147LysfsX2 (N1147KfsX2) at the protein level. The normal sequence, with the base that is duplicated in brackets, is GAAAAAA[dupA]TGAC. The duplication causes a frameshift which changes an Asparagine to a Lysine at codon 1147, and creates a premature stop codon at position 2 of the new reading frame. Due to the position of the variant, nonsense mediated decay is not expected to occur, but the variant might cause loss of normal protein function through protein truncation. The disrupted region at the end of the gene is conserved across species and is not located in a known functional domain. This variant has not, to our knowledge, been reported in the literature. Based on currently available evidence, it is unclear whether this duplication is a pathogenic variant or a benign variant. We consider it to be a variant of uncertain significance.

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