Submissions for variant NM_032043.3(BRIP1):c.2899del (p.Glu967fs)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003073795	SCV003448341	likely pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2024-09-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu967Argfs*18) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 283 amino acid(s) of the BRIP1 protein. This variant is not present in population databases (gnomAD no frequency). 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: 2140829). This variant disrupts the TopBP1-binding region of the BRIP1 protein, which plays a critical role in RPA chromatin loading and the activation of the replication checkpoint in response to DNA damage (PMID: 20159562, 21127055). While functional studies have not been performed to directly test the effect of this variant on BRIP1 protein function, this suggests that disruption of this region of the protein is causative of disease. 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.
Myriad Genetics, Inc.	RCV003316882	SCV004018203	pathogenic	Familial cancer of breast	2023-03-15	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	RCV003316882	SCV004214757	likely pathogenic	Familial cancer of breast	2023-09-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004070233	SCV005029236	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-01	criteria provided, single submitter	clinical testing	The c.2899delG variant, located in coding exon 18 of the BRIP1 gene, results from a deletion of one nucleotide at nucleotide position 2899, causing a translational frameshift with a predicted alternate stop codon (p.E967Rfs*18). This alteration occurs at the 3' terminus of theBRIP1 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 22.6% 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.