ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3401del (p.Pro1134fs) (rs756853672)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205001 SCV000261834 likely pathogenic Familial cancer of breast; Fanconi anemia, complementation group J 2018-06-08 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 20 of the BRIP1 mRNA (c.3401delC), causing a frameshift at codon 1134. This creates a premature translational stop signal in the last exon of the BRIP1 mRNA (p.Pro1134Leufs*16). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 116 amino acids of the BRIP1 protein. The frequency data for this variant (rs756853672) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has been reported in individuals with breast and/or ovarian cancer and unaffected control individuals (PMID: 20616022, 16280053, 26921362, 26315354). 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 RCV000732737 SCV000279479 uncertain significance not provided 2015-10-06 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRIP1 is denoted c.3401delC at the cDNA level and p.Pro1134LeufsX16 (P1134LfsX16) at the protein level. The normal sequence, with the base that is deleted in braces, is ACAC[C]TGAA. The deletion causes a frameshift, which changes a Proline to a Leucine at codon 1134 in the last exon of the protein, exon 20, and creates a premature stop codon at position 16 of the new reading frame. The last 117 amino acids of the protein are replaced by 16 incorrect amino acids, the clinical significance of which is unclear. BRIP1 Pro1134LeufsX16 has been observed in at least one individual with breast cancer and one individual with ovarian cancer (Lewis 2005, Walsh 2010). The lost region is not within any known functional domain. This variant was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. No mutations have been reported in the lost region, to our knowledge. Based on currently available information, it is unclear whether this deletion is a pathogenic variant or a benign variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000732737 SCV000860721 uncertain significance not provided 2018-04-13 criteria provided, single submitter clinical testing
Color RCV000772027 SCV000904989 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000772027 SCV001181660 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-08 criteria provided, single submitter clinical testing Insufficient evidence

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.