ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2854A>G (p.Ile952Val) (rs200239986)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215700 SCV000277228 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000215700 SCV000910923 likely benign Hereditary cancer-predisposing syndrome 2015-12-02 criteria provided, single submitter clinical testing
Counsyl RCV000662447 SCV000784918 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-02-14 criteria provided, single submitter clinical testing
GeneDx RCV000214349 SCV000278903 uncertain significance not provided 2018-06-13 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2854A>G at the cDNA level, p.Ile952Val (I952V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant has been identified in at least two breast cancer patients, as well as in one individual with head and neck cancer (Lu 2015, Kim 2016). BRIP1 Ile952Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the BRCA1 binding domain (Cantor 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRIP1 Ile952Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000227974 SCV000291026 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 952 of the BRIP1 protein (p.Ile952Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs200239986, ExAC 0.03%). This variant has been reported in individuals affected with breast cancer and with head and neck squamous cell carcinoma (PMID: 26790966, 26689913). ClinVar contains an entry for this variant (Variation ID: 232950). 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.
Mendelics RCV000709536 SCV000839362 uncertain significance Fanconi anemia, complementation group J 2018-07-02 criteria provided, single submitter clinical testing

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