ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1048T>C (p.Cys350Arg) (rs876658173)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214181 SCV000273080 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000483983 SCV000567040 uncertain significance not provided 2019-01-17 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1048T>C at the cDNA level, p.Cys350Arg (C350R) at the protein level, and results in the change of a Cysteine to an Arginine (TGT>CGT). In an ovarian cancer case-control meta-analysis by Ramus et al. (2015), this variant occurred in 1/3,431 controls, and was not observed in the 3,236 individuals with epithelial ovarian cancer. BRIP1 Cys350Arg was not observed in large population cohorts (Lek 2016). This variant is located within the Cys in iron-sulfur motif (Rudolf 2006). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRIP1 Cys350Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000549174 SCV000633529 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2017-03-05 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 350 of the BRIP1 protein (p.Cys350Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 229753). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000214181 SCV000904629 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-19 criteria provided, single submitter clinical testing

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