Submissions for variant NM_032043.3(BRIP1):c.2947dup (p.Ile983fs)

dbSNP: rs774684620

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470250	SCV000547362	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2023-07-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile983Asnfs*19) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 267 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs774684620, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 407863). This variant disrupts a region of the BRIP1 protein in which other variant(s) (p.Lys998Glufs*60) have been determined to be pathogenic (PMID: 18628483, 21345144; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000580476	SCV000684238	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-04-03	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide 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). Although functional studies have not been reported for this variant, this variant is expected to impair important BRIP1 protein function. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/250646 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRIP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV003335333	SCV004044174	pathogenic	Familial cancer of breast	2023-06-07	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV003335333	SCV004211374	likely pathogenic	Familial cancer of breast	2021-07-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000580476	SCV005029197	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-06	criteria provided, single submitter	clinical testing	The c.2947dupA variant, located in coding exon 19 of the BRIP1 gene, results from a duplication of A at nucleotide position 2947, causing a translational frameshift with a predicted alternate stop codon (p.I983Nfs*19). This alteration has been observed in individual(s) with a personal and/or family history of breast cancer (Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; Fostira F et al. J Med Genet, 2020 Jan;57:53-61; Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). This alteration occurs at the 3' terminus of theBRIP1 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 21% of the protein. The exact functional effect of this alteration is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.