ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3275C>T (p.Pro1092Leu) (rs587780830)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130186 SCV000185023 likely benign Hereditary cancer-predisposing syndrome 2016-10-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Color RCV000130186 SCV000903041 likely benign Hereditary cancer-predisposing syndrome 2017-02-16 criteria provided, single submitter clinical testing
Counsyl RCV000662393 SCV000784806 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2016-12-14 criteria provided, single submitter clinical testing
GeneDx RCV000442394 SCV000512424 likely benign not specified 2017-11-01 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000442394 SCV000917080 uncertain significance not specified 2018-05-21 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.3275C>T (p.Pro1092Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.8e-06 in 256466 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRIP1 causing Hereditary Breast and Ovarian Cancer (7.8e-06 vs 6.3e-05), allowing no conclusion about variant significance. c.3275C>T has been reported in the literature in individuals affected with Breast Cancer. 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, with two classifying the variant as likely benign and one as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000123358 SCV000166681 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-05-01 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1092 of the BRIP1 protein (p.Pro1092Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected in breast cancer (PMID: 26921362). ClinVar contains an entry for this variant (Variation ID: 136149). 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 leucine 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, this variant has uncertain impact on BRIP1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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