ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.638A>G (p.His213Arg) (rs376760085)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166239 SCV000217019 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-21 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000205783 SCV000260805 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-11-29 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 213 of the BRIP1 protein (p.His213Arg). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs376760085, <0.01%) but has not been reported in the literature. ClinVar contains an entry for this variant (Variation ID: 186617). 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, this is a rare missense change that is not predicted to affect protein function or cause disease. However the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000217577 SCV000278895 uncertain significance not provided 2018-04-12 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.638A>G at the cDNA level, p.His213Arg (H213R) at the protein level, and results in the change of a Histidine to an Arginine (CAC>CGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 His213Arg 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 His213Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000166239 SCV000684297 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001194200 SCV001363547 uncertain significance not specified 2019-05-06 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.638A>G (p.His213Arg) results in a non-conservative amino acid change located in the Helicase superfamily 1/2, ATP-binding domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 249704 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.638A>G, has been reported in the literature in one individual affected with colorectal cancer (Ross_2018). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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.