ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1754C>A (p.Ala585Glu) (rs756946068)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219324 SCV000276396 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-08 criteria provided, single submitter clinical testing Rarity in general population databases (dbSNP, ESP, 1000 Genomes);Insufficient or Conflicting Evidence
Integrated Genetics/Laboratory Corporation of America RCV000589026 SCV000699675 uncertain significance not provided 2017-01-10 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.1754C>A (p.Ala585Glu) variant causes a missense change involving a non-conserved nucleotide, which 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 3/121384 (1/40469), predominantly in the Latino cohort, 3/11576 (1/3858), which does exceed the estimated maximal expected allele frequency for a pathogenic BRIP1 variant of 1/16000. Therefore, suggesting this is likely a benign polymorphism found in population(s) of Latino origin. However, this observation does need to be cautiously considered due to the ExAC cohort harboring individuals that could have a BRIP1 phenotype. The variant of interest has not been, to our knowledge, reported in affected individuals via publications, although a clinical diagnostic laboratory classifies the variant as "uncertain significance." Therefore, until additional information becomes available, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Invitae RCV000636131 SCV000757563 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-08-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with glutamic acid at codon 585 of the BRIP1 protein (p.Ala585Glu). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is present in population databases (rs756946068, ExAC 0.03%). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 232300). 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. 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.
Color RCV000219324 SCV000903443 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-16 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002260 SCV001160136 uncertain significance Fanconi anemia, complementation group J 2018-12-19 criteria provided, single submitter clinical testing The BRIP1 c.1754C>A; p.Ala585Glu variant (rs756946068), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 232300). This variant is found on eight chromosomes in the Latino population in the Genome Aggregation Database. The alanine at codon 585 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Ala585Glu variant is uncertain at this time.

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