ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.533C>T (p.Thr178Ile) (rs876658780)

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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 RCV000219733 SCV000274467 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-28 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000478045 SCV000571432 uncertain significance not provided 2018-02-15 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.533C>T at the cDNA level, p.Thr178Ile (T178I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant was observed in 1/3236 serous ovarian cancer cases and 0/3431 controls (Ramus 2015), and in at least one individual meeting NCCN guidelines for BRCA testing based on their personal and/or family history of cancer (Yadav 2017). BRIP1 Thr178Ile 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 Thr178Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000555022 SCV000633701 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 178 of the BRIP1 protein (p.Thr178Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. 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: 230797). 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: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Color RCV000219733 SCV000689401 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-04 criteria provided, single submitter clinical testing

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