ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.332C>A (p.Pro111Gln) (rs201790351)

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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 RCV000222664 SCV000275567 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000222664 SCV000684256 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-08 criteria provided, single submitter clinical testing
GeneDx RCV000160339 SCV000210842 uncertain significance not provided 2016-06-20 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.332C>A at the cDNA level, p.Pro111Gln (P111Q) at the protein level, and results in the change of a Proline to a Glutamine (CCA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Pro111Gln was not observed at significant allele frequency in 1000 Genomes. Since Proline and Glutamine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Pro111Gln occurs at a position that is conserved in mammals and is located in the Helicase ATP-binding domain (Cantor 2011, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRIP1 Pro111Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000226236 SCV000291040 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces proline with glutamine at codon 111 of the BRIP1 protein (p.Pro111Gln). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 182349). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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