ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2071A>C (p.Ile691Leu) (rs587782356)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131304 SCV000186276 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient evidence
Color RCV000131304 SCV000689311 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Counsyl RCV000409629 SCV000490093 uncertain significance Fanconi anemia, complementation group J 2016-11-03 criteria provided, single submitter clinical testing
Counsyl RCV000410807 SCV000490094 uncertain significance Neoplasm of ovary 2016-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000212317 SCV000210848 uncertain significance not provided 2017-12-22 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2071A>C at the cDNA level, p.Ile691Leu (I691L) at the protein level, and results in the change of an Isoleucine to a Leucine (ATT>CTT). This variant has been observed in at least two patients with breast cancer; however, it has also been observed in a cancer free control (Ramus 2015, Easton 2016, Tung 2016). BRIP1 Ile691Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRIP1 Ile691Leu is located in the helicase domain IV (Cantor 2001). 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 Ile691Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000229910 SCV000291001 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with leucine at codon 691 of the BRIP1 protein (p.Ile691Leu). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 26921362, 26976419), and an unaffected control individual (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 142280). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

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