ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.791G>A (p.Arg264Gln) (rs758360637)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000551521 SCV000633715 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-11-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 264 of the BRIP1 protein (p.Arg264Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs758360637, 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: 461184). 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.
Ambry Genetics RCV000572564 SCV000661485 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-29 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000572564 SCV000910007 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001192825 SCV001361200 uncertain significance not specified 2019-11-05 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.791G>A (p.Arg264Gln) results in a conservative amino acid change located in the Helicase-like, DEXD box c2 type domain (IPR006554) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251072 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.791G>A has been reported in the literature in an individual affected with Breast Cancer (Tung_2015). However, this report does not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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