ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2726T>G (p.Leu909Arg) (rs770966270)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000392670 SCV000329161 uncertain significance not provided 2015-07-16 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2726T>G at the cDNA level and p.Leu909Arg (L909R) at the protein level, and results in the change of a Leucine to an Arginine (CTT>CGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Leu909Arg occurs at a position that is not conserved and is located in the region that interacts with BRCA1 (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRIP1 Leu909Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000462258 SCV000547318 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-10-09 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 909 of the BRIP1 protein (p.Leu909Arg). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 279710). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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