ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2180C>T (p.Pro727Leu) (rs876659309)

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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 RCV000219308 SCV000275629 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000469514 SCV000547244 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2017-12-19 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 727 of the BRIP1 protein (p.Pro727Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. 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: 231703). 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.
GeneDx RCV000481353 SCV000566326 uncertain significance not provided 2018-11-13 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2180C>T at the cDNA level, p.Pro727Leu (P727L) at the protein level, and results in the change of a Proline to a Leucine (CCA>CTA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRIP1 Pro727Leu was not observed 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 a deleterious effect. Based on currently available evidence, it is unclear whether BRIP1 Pro727Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000219308 SCV000904816 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-11 criteria provided, single submitter clinical testing

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