ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000457123 SCV000547303 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-12-06 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.
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.
Ambry Genetics RCV000565299 SCV000668928 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-30 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000565299 SCV000684201 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000120398 SCV001372370 uncertain significance not specified 2020-06-15 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.2284C>T (p.Arg762Cys) results in a non-conservative amino acid change located in the ATP-dependent helicase, C-terminal domain (IPR006555) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251186 control chromosomes (gnomAD). In addition, this variant has also been reported in one heterozygous individual in Flossies database (Flossies/ Weber-Lassalle _2018). This database consists of individuals who are older than age 70 but never had cancer. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2284C>T in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
ITMI RCV000120398 SCV000084550 not provided not specified 2013-09-19 no assertion provided reference population

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.