ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2440C>G (p.Arg814Gly) (rs201869624)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483176 SCV000566370 uncertain significance not provided 2015-05-01 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2440C>G at the cDNA level, p.Arg814Gly (R814G) at the protein level, and results in the change of an Arginine to a Glycine (CGT>GGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Arg814Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Arg814Gly occurs at a position that is conserved in mammals and is within the 6th ATPase/helicase motif (Cantor 2011). While protein-based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, multiple splicing models predict that this variant may create a cryptic splice donor site and possibly lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available information, it is unclear whether BRIP1 Arg814Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000567310 SCV000666252 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000801683 SCV000941472 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-08-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 814 of the BRIP1 protein (p.Arg814Gly). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and glycine. 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: 418941). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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