ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1187A>G (p.His396Arg) (rs996493095)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000456902 SCV000547363 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 396 of the BRIP1 protein (p.His396Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. 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, but has been reported in two unaffected individuals (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 407864). 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 disruptive, 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.
GeneDx RCV000483663 SCV000565989 uncertain significance not provided 2018-07-06 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1187A>G at the cDNA level, p.His396Arg (H396R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). BRIP1 His396Arg was observed in two healthy controls (2/3431) but no cases (0/3236) of epithelial ovarian cancer (Ramus 2015). BRIP1 His396Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRIP1 His396Arg is located in the helicase domain II (Cantor 2001). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRIP1 His396Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000568743 SCV000661470 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-30 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000568743 SCV000904243 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-16 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483663 SCV001133999 uncertain significance not provided 2019-04-02 criteria provided, single submitter clinical testing

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