ClinVar Miner

Submissions for variant NM_032043.3(BRIP1):c.3125_3128dup (p.Ser1043fs)

dbSNP: rs2061318885
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001179653 SCV001344363 likely pathogenic Hereditary cancer-predisposing syndrome 2023-07-10 criteria provided, single submitter clinical testing This variant inserts 4 nucleotides in exon 20 of the BRIP1 gene, creating a frameshift and premature translation stop signal in the last exon. This variant is expected to escape nonsense-mediated decay and be expressed as a truncated protein that lacks the functional domains involved in BRCA1-binding, DNA damage and replication stress responses and attenuation of DNA damage tolerance pathway (PMID: 11301010, 14983014, 20159562, 20173781, 22792074). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Multiple truncation variants that occur downstream of this variant are reported as disease-causing in ClinVar (e.g., c.3390_3393del (p.Tyr1131Leufs*18), ClinVar Variation ID: 229712). Loss of BRIP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Ambry Genetics RCV001179653 SCV003859880 uncertain significance Hereditary cancer-predisposing syndrome 2022-11-16 criteria provided, single submitter clinical testing The c.3125_3128dupAAAG variant, located in coding exon 19 of the BRIP1 gene, results from a duplication of AAAG at nucleotide position 3125, causing a translational frameshift with a predicted alternate stop codon (p.S1043Rfs*3). This alteration occurs at the 3' terminus of theBRIP1 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 207 amino acids of the protein. The exact functional effect of this alteration is unknown. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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