ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1973G>A (p.Arg658Gln) (rs759142191)

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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 RCV000575276 SCV000664828 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000575276 SCV000689303 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781168 SCV000919047 uncertain significance not specified 2018-02-26 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.1973G>A (p.Arg658Gln) results in a conservative amino acid change located in the Helical and beta-bridge domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. This frequency is not significantly higher than expected for a pathogenic variant in BRIP1 causing Hereditary Breast and Ovarian Cancer (1.2e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.1973G>A has been reported in the literature in affected individual. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000460306 SCV000547372 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-09-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 658 of the BRIP1 protein (p.Arg658Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs759142191, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 407868). 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 glutamine 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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