ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1467T>G (p.Ile489Met) (rs587780230)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000116129 SCV000186233 uncertain significance Hereditary cancer-predisposing syndrome 2016-10-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000116129 SCV000684134 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-29 criteria provided, single submitter clinical testing
GeneDx RCV000588035 SCV000150038 uncertain significance not provided 2017-09-05 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1467T>G at the cDNA level, p.Ile489Met (I489M) at the protein level, and results in the change of an Isoleucine to a Methionine (ATT>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Ile489Met was was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Methionine share similar properties, this is considered a conservative amino acid substitution. BRIP1 Ile489Met occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRIP1 Ile489Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588035 SCV000699666 uncertain significance not provided 2017-05-08 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.1467T>G (p.Ile489Met) variant involves the alteration of a non-conserved nucleotide and 2/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome for this variant. However, these predictions have yet to be functionally assessed. This variant was found in 2/82806 control chromosomes at a frequency of 0.0000242, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625). In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. 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.
Invitae RCV000462892 SCV000547295 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-11-08 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 489 of the BRIP1 protein (p.Ile489Met). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs587780230, ExAC 0.005%). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 128161). 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: "Deleterious"; 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.