ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2686A>G (p.Ile896Val) (rs764406913)

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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 RCV000222623 SCV000276334 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-08 criteria provided, single submitter clinical testing Insufficient or Conflicting Evidence
Invitae RCV000458509 SCV000547383 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-10-02 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 896 of the BRIP1 protein (p.Ile896Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs764406913, ExAC 0.03%). This variant has been observed in individuals affected with acute myeloid leukemia (PMID: 30998136). ClinVar contains an entry for this variant (Variation ID: 232249). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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 RCV000481975 SCV000573142 uncertain significance not provided 2017-02-06 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2686A>G at the cDNA level, p.Ile896Val (I896V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a lung carcinoma (Jiang 2016). BRIP1 Ile896Val was observed at an allele frequency of 0.035% (3/8654) in individuals of East Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. BRIP1 Ile896Val occurs at a position that is not conserved and is located in the BRCA1 binding domain (Cantor 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRIP1 Ile896Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481975 SCV000887990 uncertain significance not provided 2017-10-20 criteria provided, single submitter clinical testing
Color RCV000222623 SCV000902930 likely benign Hereditary cancer-predisposing syndrome 2015-04-29 criteria provided, single submitter clinical testing

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