ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3240dup (p.Ala1081fs) (rs779741278)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000398289 SCV000404577 uncertain significance BRIP1-Related Disorders 2019-04-05 criteria provided, single submitter clinical testing The BRIP1 c.3240dupT (p.Ala1081CysfsTer5) 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 0.00012 in the East Asian population from the Exome Aggregation Consortium but this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. 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, the p.Ala1081CysfsTer5 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.
Counsyl RCV000576538 SCV000677874 likely pathogenic Fanconi anemia, complementation group J; Neoplasm of ovary 2017-02-02 criteria provided, single submitter clinical testing
Color RCV000579524 SCV000684251 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-02 criteria provided, single submitter clinical testing
GeneDx RCV000657450 SCV000779185 uncertain significance not provided 2018-01-11 criteria provided, single submitter clinical testing This duplication of one nucleotide in BRIP1 is denoted c.3240dupT at the cDNA level and p.Ala1081CysfsX5 (A1081CfsX5) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TTGA[dupT]GCCA. The duplication causes a frameshift which changes an Alanine to a Cysteine at codon 1081, and creates a premature stop codon at position 5 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 not located in a known functional domain. This variant has been reported in at least one individual with sarcoma, who also carried BRIP1 Glu767Asp (Ballinger 2016). 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.
Ambry Genetics RCV000579524 SCV001180738 likely pathogenic Hereditary cancer-predisposing syndrome 2018-02-19 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Other data supporting pathogenic classification
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030465 SCV001193525 likely pathogenic Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Invitae RCV001063687 SCV001228546 likely pathogenic Familial cancer of breast; Fanconi anemia, complementation group J 2019-12-11 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the BRIP1 gene (p.Ala1081Cysfs*5). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 169 amino acids of the BRIP1 protein. This variant is present in population databases (rs779741278, ExAC 0.01%). This variant has been observed in an individual with sarcoma (PMID: 27498913). ClinVar contains an entry for this variant (Variation ID: 324348). 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.
Leiden Open Variation Database RCV000657450 SCV001364530 uncertain significance not provided 2019-08-13 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.

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