ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3230T>G (p.Leu1077Ter) (rs1420431000)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000776642 SCV000912262 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-12 criteria provided, single submitter clinical testing
Invitae RCV000636085 SCV000757517 likely pathogenic Familial cancer of breast; Fanconi anemia, complementation group J 2018-04-23 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the BRIP1 gene (p.Leu1077*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 173 amino acids of the BRIP1 protein. 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 disease. This truncation affects the TopBP1-binding region (residues 1130-1153) of the BRIP1 protein. It is expected to disrupt the TopBP1-BRIP1 interaction that plays a critical role in RPA chromatin loading following DNA replication stress and the subsequent activation of the replication checkpoint in response to DNA damage (PMID: 20159562, 21127055). 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.

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