Submissions for variant NM_032043.3(BRIP1):c.2786_2789del (p.Leu929fs)

dbSNP: rs1295703239

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000636079	SCV000757511	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu929Hisfs*55) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 321 amino acid(s) of the BRIP1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 31300551). ClinVar contains an entry for this variant (Variation ID: 530300). This variant disrupts a region of the BRIP1 protein in which other variant(s) (p.Lys998Glufs*6) have been determined to be pathogenic (PMID: 18628483, 26921362, 28423363; 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	RCV001184523	SCV001350516	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-04-16	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 19 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. This variant has been reported in an individual affected with breast cancer (PMID: 31300551). This variant has been identified in 1/250646 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.
Genetic Services Laboratory, University of Chicago	RCV001194730	SCV002067344	likely pathogenic	not provided	2019-06-21	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003336101	SCV004043665	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	RCV003336101	SCV005059255	likely pathogenic	Familial cancer of breast	2024-02-10	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV001194730	SCV001364500	pathogenic	not provided	2019-12-23	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Florentia Fostira.