ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2441G>A (p.Arg814His) (rs45468199)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130375 SCV000185229 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-19 criteria provided, single submitter clinical testing The p.R814H variant (also known as c.2441G>A), located in coding exon 16 of the BRIP1 gene, results from a G to A substitution at nucleotide position 2441. The arginine at codon 814 is replaced by histidine, an amino acid with highly similar properties. This alteration was previously reported in 1/1212 BRCA1/BRCA2 mutation negative breast cancer cases and 0/2081 controls (Seal S et al. Nat. Genet., 2006 Nov;38:1239-41). This variant was also reported in 2/13213 breast cancer cases in the UK and 0/5242 controls (Easton DF et al. J. Med. Genet., 2016 May;53:298-309). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000218503 SCV000278902 uncertain significance not provided 2018-11-16 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2441G>A at the cDNA level, p.Arg814His (R814H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant was observed in individuals with breast cancer and was absent from control populations and has also been reported in at least one individual with colon cancer (Seal 2006, Easton 2016, Hampel 2018). BRIP1 Arg814His 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 Arg814His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000234009 SCV000291014 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 814 of the BRIP1 protein (p.Arg814His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs45468199, ExAC 0.005%). This variant has been reported in individuals affected with breast cancer (PMID: 17033622, 26921362). ClinVar contains an entry for this variant (Variation ID: 141744). 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.
Counsyl RCV000410258 SCV000490105 uncertain significance Fanconi anemia, complementation group J 2016-11-14 criteria provided, single submitter clinical testing
Counsyl RCV000411419 SCV000490106 uncertain significance Neoplasm of ovary 2016-11-14 criteria provided, single submitter clinical testing
Color RCV000130375 SCV000911528 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-23 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030534 SCV001193530 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research

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