ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3209C>A (p.Ser1070Ter) (rs777213170)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000459986 SCV000547352 likely pathogenic Familial cancer of breast 2017-04-23 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the BRIP1 mRNA at codon 1070 (p.Ser1070*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 180 amino acids of the BRIP1 protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a 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 on 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, this variant that is expected to disrupt a region that is essential for BRIP1 protein function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV000481412 SCV000572718 uncertain significance not provided 2017-01-11 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.3209C>A at the cDNA level and p.Ser1070Ter (S1070X) at the protein level. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TAA). Although this variant has not, to our knowledge, been published in the literature as a germline variant, it has been reported as a confirmed somatic variant in ovarian cancer (Beltrame 2015). BRIP1 Ser1070Ter results in the loss of 180 amino acids at the end of the protein, the clinical significance of which is unclear, as the lost region is not within any known functional domain. Due to the location of the newly created nonsense codon in the last exon, the transcript is not expected to undergo nonsense-mediated decay and could therefore encode a truncated protein that retains some normal function. BRIP1 Ser1070Ter was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Based on currently available evidence, it is unclear whether BRIP1 Ser1070Ter is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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