Submissions for variant NM_032043.3(BRIP1):c.3208del (p.Ser1070fs)

dbSNP: rs748598593

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000552971	SCV000633515	likely pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1070Glnfs*8) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 180 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs748598593, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast and/or endometrial cancer (PMID: 28452373, 30914433, 36451132). ClinVar contains an entry for this variant (Variation ID: 461046). 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.
Ambry Genetics	RCV001019231	SCV001180562	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-05-19	criteria provided, single submitter	clinical testing	The c.3208delT variant, located in coding exon 19 of the BRIP1 gene, results from a deletion of one nucleotide at nucleotide position 3208, causing a translational frameshift with a predicted alternate stop codon (p.S1070Qfs*8). Premature stop codons are typically deleterious in nature; however, this stop codon occurs at the 3' terminus of BRIP1, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 180 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, structural and functional analyses suggest that at least two residues contained in this deleted region (Ser1237 and Lys1249) have functional importance (Olsen JV et al. Sci Signal, 2010 Jan;3:ra3; Xie J et al. PLoS Genet., 2012 Jul;8:e1002786). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284119	SCV001469739	likely pathogenic	not provided	2020-03-20	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Not found in the total gnomAD dataset, and the data is high quality.
GeneDx	RCV001284119	SCV001778619	likely pathogenic	not provided	2019-11-27	criteria provided, single submitter	clinical testing	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 180 amino acids are lost and replaced with 7 incorrect amino acids (Stenson 2014); Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 26689913, 29922827)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235277	SCV003934045	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-05-18	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.3208delT (p.Ser1070GlnfsX8) results in a premature termination codon, and although it is not expected to undergo nonsense mediated decay, it is predicted to cause a truncation of the encoded protein, a commonly known mechanism for disease. The variant was absent in 251388 control chromosomes (gnomAD). c.3208delT has been reported in the literature in an individual affected with breast cancer and in an individual affected with endometrial cancer (Lu_2015, Kraya_2019). To our knowledge, no experimental evidence directly examining the impact of this variant on protein function has been reported. However, this variant disrupts the TopBP1-binding domain of the BRIP1 protein, including the C-terminal Thr1133 residue required for interaction with TopB1, which plays a critical role in DNA damage response (Gong_2010). The following publications have been ascertained in the context of this evaluation (PMID: 30914433, 26689913, 20159562). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003459207	SCV004214693	likely pathogenic	Familial cancer of breast	2023-10-10	criteria provided, single submitter	clinical testing