ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2038_2039dup (p.Leu680fs) (rs587778134)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000213084 SCV000885122 pathogenic not provided 2018-03-26 criteria provided, single submitter clinical testing The BRIP c.2038_2039dupTT; p.Leu680fs variant (rs587778134), also published as c.2040_2041insTT, is reported in the medical literature in individuals affected with breast or ovarian cancer (Couch 2015, Rafnar 2011, Ramus 2015, Shirts 2016, Susswein 2016). The variant is reported as pathogenic or likely pathogenic by several sources in the ClinVar database (Variation ID: 128166). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by duplicating two nucleotides causing a frameshift, and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Considering available information, this variant is classified as pathogenic. However, pathogenic variants in BRIP1 are thought to have reduced penetrance (Seal 2006). References: Couch FJ et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015 Feb 1;33(4):304-11. Rafnar T et al. Mutations in BRIP1 confer high risk of ovarian cancer. Nat Genet. 2011 Oct 2;43(11):1104-7. Ramus SJ et al. Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. J Natl Cancer Inst. 2015 Aug 27;107(11). Seal S et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet. 2006 Nov;38(11):1239-41. Shirts BH et al. Improving performance of multigene panels for genomic analysis of cancer predisposition. Genet Med. 2016 Oct;18(10):974-81. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32.
Ambry Genetics RCV000116134 SCV000185786 pathogenic Hereditary cancer-predisposing syndrome 2017-05-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000116134 SCV000911176 pathogenic Hereditary cancer-predisposing syndrome 2017-10-20 criteria provided, single submitter clinical testing
Counsyl RCV000409330 SCV000489855 likely pathogenic Fanconi anemia, complementation group J 2016-08-10 criteria provided, single submitter clinical testing
Counsyl RCV000409984 SCV000489856 likely pathogenic Neoplasm of ovary 2016-08-10 criteria provided, single submitter clinical testing
GeneDx RCV000213084 SCV000150043 pathogenic not provided 2017-05-24 criteria provided, single submitter clinical testing This duplication of 2 nucleotides in BRIP1 is denoted c.2038_2039dupTT at the cDNA level and p.Leu680PhefsX9 (L680FfsX9) at the protein level. The normal sequence, with the bases that are duplicated in braces, is ACTT{TT}GTTA. The duplication causes a frameshift which changes a Leucine to a Phenylalanine at codon 680, and creates a premature stop codon at position 9 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been observed in association with breast and ovarian cancer (Couch 2015, Ramus 2015). We consider BRIP1 c.2038_2039dupTT to be pathogenic.
ITMI RCV000120393 SCV000084545 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000469530 SCV000547370 pathogenic Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu680Phefs*9) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 25452441, 26681312, 26845104, 26315354, 21964575). This variant is also known as c.2040_ 2041insTT in the literature. ClinVar contains an entry for this variant (Variation ID: 128166). Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000213084 SCV000889204 pathogenic not provided 2017-09-29 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000116134 SCV000266057 pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing

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