ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.823A>G (p.Ile275Val) (rs587781425)

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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 RCV000129307 SCV000184069 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000129307 SCV000684306 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-13 criteria provided, single submitter clinical testing
Counsyl RCV000663199 SCV000786375 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2018-04-19 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000473432 SCV000895113 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000485268 SCV000566817 uncertain significance not provided 2017-11-09 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.823A>G at the cDNA level, p.Ile275Val (I275V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant has been reported in at least one BRCA1/2 negative individual with breast cancer, but also in at least one control (Guenard 2008, Ramus 2015). BRIP1 Ile275Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. BRIP1 Ile275Val is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether BRIP1 Ile275Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000473432 SCV000547282 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 275 of the BRIP1 protein (p.Ile275Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs587781425, ExAC 0.006%). This variant has been reported in an individual affected with breast cancer (PMID: 18414782), as well as in an unaffected individual (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 140995). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.

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