ClinVar Miner

Submissions for variant NM_032043.3(BRIP1):c.317G>A (p.Arg106His)

gnomAD frequency: 0.00048  dbSNP: rs143615668
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131589 SCV000186601 likely benign Hereditary cancer-predisposing syndrome 2018-10-09 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Invitae RCV001082225 SCV000253628 likely benign Familial cancer of breast; Fanconi anemia complementation group J 2021-12-17 criteria provided, single submitter clinical testing
GeneDx RCV000588637 SCV000278891 likely benign not provided 2021-06-08 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26921362, 28382101, 27978560, 23555315, 28767289, 26689913, 27535533)
Genetic Services Laboratory,University of Chicago RCV000220020 SCV000593769 likely benign not specified 2017-03-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000220020 SCV000699715 benign not specified 2019-10-04 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.317G>A (p.Arg106His) results in a non-conservative amino acid change located in the ATP-binding domain (IPR014013, IPR014001) and the c2 type DEXD box domain (IPR006554) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 282850 control chromosomes, predominantly at a frequency of 0.0014 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 22 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRIP1 causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05). In addition, this variant was found in 9/2559 African American individuals who are cancer free and older than age 70. These data strongly suggest that the variant is a benign polymorphism found primarily in populations of African origin. c.317G>A has been reported in the literature in individuals affected with various tumor phenotypes (Pearlman 2016, Shindo 2017), however in one of these cases a patient with colorectal cancer also carried a known pathogenic APC variant (c.1759del/p.S587Afs*3, Pearlman 2016). Therefore these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as Benign (1x), Likely benign (4x) or VUS (1x). Based on the evidence outlined above, the variant was classified as benign.
Counsyl RCV000663050 SCV000786100 uncertain significance Fanconi anemia complementation group J; Neoplasm of ovary 2018-02-21 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000131589 SCV000910802 benign Hereditary cancer-predisposing syndrome 2015-09-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588637 SCV001134024 likely benign not provided 2021-05-17 criteria provided, single submitter clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State RCV002225445 SCV002505051 benign Hereditary breast ovarian cancer syndrome 2022-04-19 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000131589 SCV002533679 likely benign Hereditary cancer-predisposing syndrome 2021-07-29 criteria provided, single submitter curation

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