ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1207C>T (p.Arg403Trp) (rs369631413)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123346 SCV000166669 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-09-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 403 of the BRIP1 protein (p.Arg403Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs369631413, ExAC 0.01%). This variant has been reported in the literature in an individual affected with breast cancer (PMID: 25452441). ClinVar contains an entry for this variant (Variation ID: 136141). 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 C15"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000215569 SCV000273976 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000343344 SCV000329156 uncertain significance not provided 2017-09-08 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1207C>T at the cDNA level, p.Arg403Trp (R403W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has been reported in at least two individuals with triple negative breast cancer (Couch 2015). Additionally, this variant was also observed in a breast cancer case-control study, with an observation in 1/5242 controls and was absent in the 13,213 breast cancer cases (Easton 2016). BRIP1 Arg403Trp was observed at an allele frequency of 0.012% (8/66610) in individuals of European (Non-Finnish) ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Arg403Trp occurs at a position that is conserved across species and is not located in 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 Arg403Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000411604 SCV000489923 uncertain significance Fanconi anemia, complementation group J 2016-08-09 criteria provided, single submitter clinical testing
Counsyl RCV000409639 SCV000489924 uncertain significance Neoplasm of ovary 2016-08-09 criteria provided, single submitter clinical testing
Color RCV000215569 SCV000684118 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000343344 SCV000887976 uncertain significance not provided 2017-08-09 criteria provided, single submitter clinical testing

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