ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1165G>A (p.Val389Ile) (rs587780825)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123345 SCV000166668 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-04-09 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 389 of the BRIP1 protein (p.Val389Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 136140). 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 isoleucine 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.
Ambry Genetics RCV000219844 SCV000278632 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence
GeneDx RCV000521223 SCV000618424 uncertain significance not provided 2017-12-18 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1165G>A at the cDNA level, p.Val389Ile (V389I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Val389Ile was not observed in large population cohorts (Lek 2016). Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. BRIP1 Val389Ile is located in the Helicase Domain II (Cantor 2011). 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 Val389Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000219844 SCV000908258 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing

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