ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2284C>T (p.Arg762Cys) (rs587778136)

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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 RCV000565299 SCV000668928 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000565299 SCV000684201 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-19 criteria provided, single submitter clinical testing
GeneDx RCV000657037 SCV000567096 uncertain significance not provided 2019-01-03 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2284C>T at the cDNA level, p.Arg762Cys (R762C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant was observed in 1 out of 36,687 healthy controls and absent in 706 ovarian cancer patients and 6,341 breast cancer patients (Weber-Lassalle 2018). BRIP1 Arg762Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the helicase domain V (Cantor 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRIP1 Arg762Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000120398 SCV000084550 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000457123 SCV000547303 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 762 of the BRIP1 protein (p.Arg762Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs587778136, ExAC 0.006%). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 133754). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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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