ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3390_3393delCTAT (rs778664039)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219431 SCV000273024 likely pathogenic Hereditary cancer-predisposing syndrome 2018-04-03 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),Other strong data supporting pathogenic classification
Illumina Clinical Services Laboratory,Illumina RCV000396476 SCV000404574 uncertain significance BRIP1-Related Disorders 2017-04-27 criteria provided, single submitter clinical testing The BRIP1 c.3390_3393delCTAT (p.Tyr1131LeufsTer18) variant results in a frameshift, and is predicted to result in premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.00008 in the European (non-Finnish) population from the Exome Aggregation Consortium. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for BRIP1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000589475 SCV000565791 uncertain significance not provided 2017-10-25 criteria provided, single submitter clinical testing This deletion of 4 nucleotides in BRIP1 is denoted c.3390_3393delCTAT at the cDNA level and p.Tyr1131LeufsX18 (Y1131LfsX18) at the protein level. The normal sequence, with the bases that are deleted in braces, is CTAT[CTAT]TTTA. This deletion causes a frameshift, which changes a Tyrosine to a Leucine at codon 1131, and creates a premature stop codon at position 18 of the new reading frame, resulting in the loss of 119 correct amino acids and the gain of 17 incorrect ones. Although this variant results in a frameshift, it is located far 3Â’ in the last exon of the BRIP1 gene making the effect on the protein unclear. The disrupted region is not located within any known functional domain (Cantor 2011). While this variant has not, to our knowledge, been published in the literature as a germline pathogenic or benign variant, another far 3' frameshift variant, BRIP1 c.3401delC, has been observed in at least two individuals with a personal history of either breast or ovarian cancer (Lewis 2005, Walsh 2010). However, Lewis et al. (2005) showed that this variant did not segregate with the reported breast cancer in one family. Based on current information, it is unclear whether BRIP1 c.3390_3393delCTAT is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000543566 SCV000633669 likely pathogenic Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-16 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the BRIP1 gene (p.Tyr1131Leufs*18). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 119 amino acids of the BRIP1 protein. This variant is present in population databases (rs778664039, ExAC 0.009%). This variant has been reported in an individual affected with prostate cancer (PMID: 27701467). This variant is also known as p.I1130fs in the literature. ClinVar contains an entry for this variant (Variation ID: 229712). 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, 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.
Counsyl RCV000576546 SCV000677837 likely pathogenic Fanconi anemia, complementation group J; Neoplasm of ovary 2016-11-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589475 SCV000699721 uncertain significance not provided 2015-11-25 criteria provided, single submitter clinical testing
Color RCV000219431 SCV000903022 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-26 criteria provided, single submitter clinical testing

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