ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2593C>T (p.Arg865Trp) (rs578022079)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000217245 SCV000273828 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000228828 SCV000291018 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 865 of the BRIP1 protein (p.Arg865Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs578022079, ExAC 0.006%). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 230320). 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 disruptive, but 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.
GeneDx RCV000586310 SCV000329159 uncertain significance not provided 2018-01-29 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2593C>T at the cDNA level, p.Arg865Trp (R865W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Arg865Trp was not observed at significant allele frequency in large population cohorts (Lek 2016). BRIP1 Arg865Trp is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRIP1 Arg865Trp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000217245 SCV000684226 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586310 SCV000699699 uncertain significance not provided 2016-11-18 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.2593C>T (p.Arg865Trp) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant was found in 1/120118 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Counsyl RCV000662563 SCV000785165 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-05-17 criteria provided, single submitter clinical testing
Mendelics RCV000709537 SCV000839364 uncertain significance Fanconi anemia, complementation group J 2018-07-02 criteria provided, single submitter clinical testing

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