ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2706A>G (p.Ile902Met) (rs587780244)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000116148 SCV000184658 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000116148 SCV000903015 likely benign Hereditary cancer-predisposing syndrome 2015-11-24 criteria provided, single submitter clinical testing
Counsyl RCV000410789 SCV000489951 uncertain significance Fanconi anemia, complementation group J 2016-08-22 criteria provided, single submitter clinical testing
Counsyl RCV000412341 SCV000489952 uncertain significance Neoplasm of ovary 2016-08-22 criteria provided, single submitter clinical testing
GeneDx RCV000656814 SCV000150057 uncertain significance not provided 2018-02-13 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2706A>G at the cDNA level, p.Ile902Met (I902M) at the protein level, and results in the change of an Isoleucine to a Methionine (ATA>ATG). This variant was observed in at least one individual with advanced cancer; however, the type was not specified (Mandelker 2017). BRIP1 Ile902Met 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 Ile902Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000229209 SCV000291021 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-10-25 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 902 of the BRIP1 protein (p.Ile902Met). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs587780244, ExAC 0.003%). This variant has been reported in an individual affected with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 128179). 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 methionine 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212329 SCV000600906 uncertain significance not specified 2017-07-17 criteria provided, single submitter clinical testing

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