ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1688A>G (p.Asp563Gly) (rs577768294)

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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 RCV000218250 SCV000276224 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: in silico models in agreement (benign),Insufficient or Conflicting Evidence,Rarity in general population databases (dbSNP, ESP, 1000 Genomes)
Color RCV000218250 SCV000684151 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587318 SCV000699674 uncertain significance not provided 2016-08-24 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.1688A>G (p.Asp563Gly) variant causes a missense change involving a conserved nucleotide with 2/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting 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 3/121336 (1/40485), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRIP1 variant of 1/16000. The variant of interest has been reported by multiple clinical laboratories have cited the variant as "uncertain significance." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Invitae RCV000227822 SCV000290983 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 563 of the BRIP1 protein (p.Asp563Gly). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs577768294, 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: 232167). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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