ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1684A>G (p.Ile562Val) (rs45533636)

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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 RCV000160342 SCV000215469 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000160342 SCV000911077 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
Counsyl RCV000663029 SCV000786059 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2018-02-13 criteria provided, single submitter clinical testing
GeneDx RCV000212314 SCV000210846 uncertain significance not provided 2018-02-15 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1684A>G at the cDNA level, p.Ile562Val (I562V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant was observed in an individual with a personal history of a Lynch syndrome-associated cancer and/or polyps, but was also observed in a control individual in a breast cancer case-control study (Yurgelun 2015, Easton 2016). BRIP1 Ile562Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 Ile562Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000456914 SCV000547380 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-10-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 562 of the BRIP1 protein (p.Ile562Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs45533636, ExAC 0.001%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 26315354, 17033622), colorectal cancer (PMID: 28135145), and suspected Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 182352). 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. 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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