ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2765T>G (p.Leu922Ter) (rs587782410)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131449 SCV000186433 pathogenic Hereditary cancer-predisposing syndrome 2017-05-24 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 RCV000131449 SCV000903752 pathogenic Hereditary cancer-predisposing syndrome 2018-07-09 criteria provided, single submitter clinical testing
Counsyl RCV000410978 SCV000489911 pathogenic Fanconi anemia, complementation group J 2016-08-02 criteria provided, single submitter clinical testing
Counsyl RCV000412207 SCV000489912 pathogenic Neoplasm of ovary 2016-08-02 criteria provided, single submitter clinical testing
GeneDx RCV000216847 SCV000279375 pathogenic not provided 2018-02-26 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRIP1 c.2765T>G at the cDNA level and p.Leu922Ter (L922X) at the protein level. The substitution creates a nonsense variant, which changes a Leucine to a premature stop codon (TTA>TGA) and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRIP1 Leu922Ter has been reported in at least three individuals with breast cancer (Couch 2015, Easton 2016, Weber-Lassalle 2018). This variant is considered pathogenic.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000131449 SCV000803167 pathogenic Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588116 SCV000699703 likely pathogenic Hereditary breast and ovarian cancer syndrome 2016-11-25 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.2765T>G (p.Leu922X) variant results in a premature termination codon, predicted to cause a truncated or absent BRIP1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121394, which does not exceed the estimated maximal expected allele frequency for a pathogenic BRIP1 variant of 1/16000. The variant has been reported in one triple negative breast cancer case as well as a high-risk unaffected control (Couch_2015, Ramus_2015) via publications. In addition, multiple clinical diagnostic laboratories cite the variant as "pathogenic." However, it does need to be noted, a recent publication by Easton_2016 (PMID: 26921362) indicates that the prevalence of truncating variants in BRIP1 have comparable occurrences in controls and cases, for example, p.Arg798Ter was observed in 23 cases and 18 controls, suggesting that truncating variants may not be associated with a substantial increase in breast cancer risk, although the authors do state "BRIP1 screening might have utility for ovarian cancer risk prediction, in combination with other risk factors." Therefore, the variant of interest has been classified as "Likely Pathogenic."
Invitae RCV000468535 SCV000547327 pathogenic Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 922 (p.Leu922*) of 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. This particular variant has been reported in individuals affected with breast cancer (PMID: 25452441, 26921362). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000216847 SCV000887991 pathogenic not provided 2018-06-29 criteria provided, single submitter clinical testing

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