ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.854A>G (p.His285Arg) (rs141055990)

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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 RCV000131157 SCV000186099 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000131157 SCV000903607 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-29 criteria provided, single submitter clinical testing
Counsyl RCV000411077 SCV000490037 uncertain significance Fanconi anemia, complementation group J 2016-10-06 criteria provided, single submitter clinical testing
Counsyl RCV000412159 SCV000490038 uncertain significance Neoplasm of ovary 2016-10-06 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000220964 SCV000861413 uncertain significance not provided 2018-06-05 criteria provided, single submitter clinical testing
GeneDx RCV000220964 SCV000279545 uncertain significance not provided 2017-09-25 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.854A>G at the cDNA level, p.His285Arg (H285R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). This variant has not, to our knowledge, been published in the literature as either a pathogenic or benign germline variant. However, it has been reported in a tumor sample from an individual with a recurrent pediatric solid tumor (Harris 2016). BRIP1 His285Arg was observed at an allele frequency of 0.08% (19/24,032) in individuals of African ancestry in large population cohorts (Lek 2016). Since Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. BRIP1 His285Arg occurs at a position that is conserved in mammals and is not located a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRIP1 His285Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781177 SCV000919056 likely benign not specified 2018-06-15 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.854A>G (p.His285Arg) results in a non-conservative amino acid change located in the ATP-binding domain (IPR014001) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The observed variant frequency within African control individuals in the gnomAD database is approximately 12.64 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRIP1 causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.854A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000231925 SCV000291059 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-06 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 285 of the BRIP1 protein (p.His285Arg). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs141055990, ExAC 0.08%). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 142179). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000411077 SCV000839391 uncertain significance Fanconi anemia, complementation group J 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000220964 SCV000889228 uncertain significance not provided 2018-03-07 criteria provided, single submitter clinical testing

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