ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1759C>G (p.His587Asp) (rs876660519)

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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 RCV000218989 SCV000278016 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000218989 SCV000689282 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-26 criteria provided, single submitter clinical testing
Counsyl RCV000662848 SCV000785715 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-11-15 criteria provided, single submitter clinical testing
GeneDx RCV000482369 SCV000570517 uncertain significance not provided 2018-10-15 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1759C>G at the cDNA level, p.His587Asp (H587D) at the protein level, and results in the change of a Histidine to an Aspartic Acid (CAT>GAT). In a case control study, this variant was absent from 13,213 breast cancer cases, but was found in 2/5242 controls (Easton 2016). BRIP1 His587Asp was not observed 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 a deleterious effect. Based on currently available evidence, it is unclear whether BRIP1 His587Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000473133 SCV000547265 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-09-18 criteria provided, single submitter clinical testing This sequence change replaces histidine with aspartic acid at codon 587 of the BRIP1 protein (p.His587Asp). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 233608). 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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