NM_032043.2(BRIP1):c.2258-1G>A AND not provided

Clinical significance:Likely pathogenic (Last evaluated: May 4, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description


BRIP1:BRCA1 interacting protein C-terminal helicase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • NC_000017.11:g.61743135C>T
  • NG_007409.2:g.125425G>A
  • NM_032043.2:c.2258-1G>A
  • LRG_300t1:c.2258-1G>A
  • LRG_300:g.125425G>A
  • NC_000017.10:g.59820496C>T
dbSNP: rs1064793887
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_032043.2:c.2258-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]


MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000567273GeneDxcriteria provided, single submitter
Likely pathogenic
(May 4, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000567273.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided


This pathogenic variant is denoted BRIP1 c.2258-1G>A or IVS15-1G>A and consists of a G>A nucleotide substitution at the -1 position of intron 15 of the BRIP1 gene. The variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature. Based on the current evidence, we consider BRIP1 c.2258-1G>A 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?s partner also carries a BRIP1mutation, the risk to have a child with FA is 25% with each pregnancy.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 28, 2019

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