Submissions for variant NM_032043.3(BRIP1):c.2205dup (p.Asp736Ter)

dbSNP: rs1555591385

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657812	SCV000779567	likely pathogenic	not provided	2016-01-05	criteria provided, single submitter	clinical testing	This variant is denoted BRIP1 c.2205dupT at the cDNA level and p.Asp736Ter (D736X) at the protein level. The substitution creates a nonsense variant, which changes an Aspartic Acid to a premature stop codon (GAT>TGA) , and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered likely pathogenic. BRIP1 has been only recently described in association with cancer predisposition and the risks are not well understood. The presence of a BRIP1 pathogenic variant may confer an increased risk for female breast and ovarian cancer, and possibly pancreatic (Seal 2006, Rafnar 2011, Pennington 2014). In a case-control study of BRCA-negative women with breast cancer, truncating BRIP1 pathogenic variants were identified in 0.7% (9/1,212) women with breast cancer and 0.1% (2/2,081) controls, suggesting some increased breast cancer risk (OR = 2.0, p=0.012) (Seal 2006). Pennington et al. (2014) also identified germline BRIP1 pathogenic variants in 1.1% (4/367) patients with ovarian cancer, peritoneal cancer or fallopian tube cancer. It has been hypothesized that BRIP1 may be a low penetrance allele as families with multiple cases of breast cancer found to harbor a BRIP1 pathogenic variant have shown incomplete segregation with disease (Seal 2006). Fanconi anemia (FA) is a rare autosomal recessive condition that can be caused by two pathogenic variants (one in each copy of the gene) in the BRIP1 gene (Seal 2006). This condition is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy in children including leukemia and certain solid tumors. The Fanconi anemia phenotype due to BRIP1 pathogenic variants is thought to result in a lower rate of childhood solid tumors compared to the phenotype due to two BRCA2 pathogenic variants (Apostolou 2013). If both parents carry a BRIP1 pathogenic variant, the risk to have a child with FA is 25% for each pregnancy.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000703182	SCV000832070	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2022-09-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp736*) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). 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: 546045). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003336127	SCV004045064	pathogenic	Familial cancer of breast	2023-06-06	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.