ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1465A>G (p.Ile489Val) (rs1555605855)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000563502 SCV000666237 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Integrated Genetics/Laboratory Corporation of America RCV000780060 SCV000917082 uncertain significance not specified 2018-07-31 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.1465A>G (p.Ile489Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 236224 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1465A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000693834 SCV000822255 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-08 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 489 of the BRIP1 protein (p.Ile489Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. 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: 481652). 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 valine 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.

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