Submissions for variant NM_032043.3(BRIP1):c.1889del (p.Thr630fs)

dbSNP: rs1064793626

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487110	SCV000566637	pathogenic	not provided	2015-05-19	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in BRIP1 is denoted c.1889delC at the cDNA level and p.Thr630AsnfsX58 (T630NfsX58) at the protein level. The normal sequence, with the base that is deleted in braces, is GTTA[C]ATTT. The deletion causes a frameshift, which changes a Threonine to an Asparagine at codon 630, and creates a premature stop codon at position 58 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. we consider this variant to be pathogenic.BRIP1 has been only recently described in association with cancer predisposition and the risks are not well understood. The presence of a BRIP1 mutation may confer an increased risk for female breast cancer and ovarian cancer based on currently available data (Seal 2006, Rafnar 2011, Pennington 2014). In one case-control study, truncating BRIP1 mutations were identified in 9 out of 1,212 individuals previously diagnosed with breast cancer, from BRCA-negative families, and in 2 out of 2,081 controls, suggesting an increased risk for breast cancer (OR = 2.0) (Seal 2006). Of note, BRIP1 missense variants found in this study were not associated with cancer risk. A specific frameshift variant found in an Icelandic cohort was associated with an increased risk for both ovarian and pancreatic cancer, while another frameshift variant, found in a Spanish cohort, conferred an increased risk for both breast and ovarian cancer in a study looking at sequence variants and their association with these cancer types (Rafnar 2011). Pennington et al. (2014) also identified a germline BRIP1 mutation in 4 out of 367 patients, unselected for family history, who had a personal history of ovarian cancer, peritoneal cancer or fallopian tube cancer. Of note, 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 mutation, have shown incomplete segregation with disease (Seal 2006).Fanconi Anemia (FA) is a rare autosomal recessive condition that can be caused by two mutations (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 mutations is thought to result in a lower rate of childhood solid tumors compared to the phenotype due to two BRCA2 variants (Apostolou 2013). If a BRIP1 mutation carrier'spartner also carries a BRIP1mutation, the risk to have a child with FA is 25% with each pregnancy.
Color Diagnostics, LLC DBA Color Health	RCV001188865	SCV001356023	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 13 of the BRIP1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified 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 Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001215660	SCV001387415	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr630Asnfs*58) 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: 419076). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003335350	SCV004044276	pathogenic	Familial cancer of breast	2023-06-05	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	RCV003335350	SCV005059244	likely pathogenic	Familial cancer of breast	2024-02-22	criteria provided, single submitter	clinical testing
CZECANCA consortium	RCV001271071	SCV001451897	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing