ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3651G>T (p.Trp1217Cys) (rs542698396)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129907 SCV000184725 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000227303 SCV000291046 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with cysteine at codon 1217 of the BRIP1 protein (p.Trp1217Cys). The tryptophan residue is weakly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 141402). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000657056 SCV000567861 uncertain significance not provided 2018-01-23 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.3651G>T at the cDNA level, p.Trp1217Cys (W1217C) at the protein level, and results in the change of a Tryptophan to a Cysteine (TGG>TGT). This variant has been reported in at least one individual with breast cancer undergoing multigene panel testing (Tung 2016). BRIP1 Trp1217Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRIP1 Trp1217Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483182 SCV000600918 uncertain significance not specified 2017-06-08 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000657056 SCV000807147 uncertain significance not provided 2016-11-02 criteria provided, single submitter clinical testing
Mendelics RCV000709522 SCV000839346 uncertain significance Fanconi anemia, complementation group J 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000227303 SCV000896645 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000129907 SCV000911032 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing

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