ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.205G>A (p.Gly69Arg) (rs372581879)

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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 RCV000223223 SCV000273463 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000586010 SCV000566839 uncertain significance not provided 2018-11-21 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.205G>A at the cDNA level, p.Gly69Arg (G69R) at the protein level, and results in the change of a Glycine to an Arginine (GGG>AGG). This variant was reported in a control subject but was absent in cases in a breast case-control study (Easton 2016). BRIP1 Gly69Arg was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 Gly69Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586010 SCV000699682 uncertain significance not provided 2015-11-13 criteria provided, single submitter clinical testing
Invitae RCV000549099 SCV000633589 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 69 of the BRIP1 protein (p.Gly69Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. It also falls at the last nucleotide of exon 3 of the BRIP1 coding sequence. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals undergoing hereditary cancer panel testing (PMID: 25318351). ClinVar contains an entry for this variant (Variation ID: 230053). 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. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change at the last nucleotide of the exon that is not predicted to affect protein function, but is predicted to affect RNA splicing. It has been classified as a Variant of Uncertain Significance.

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