ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1660C>G (p.Gln554Glu) (rs777217004)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000218328 SCV000277495 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-14 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000462805 SCV000547292 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 554 of the BRIP1 protein (p.Gln554Glu). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is present in population databases (rs777217004, ExAC 0.003%). This variant has been reported in families affected with breast and/or ovarian cancer (PMID: 26534844). ClinVar contains an entry for this variant (Variation ID: 233173). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional 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.
GeneDx RCV000590587 SCV000569104 uncertain significance not provided 2018-10-11 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1660C>G at the cDNA level, p.Gln554Glu (Q554E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAG>GAG). This variant has been reported in at least one individual with breast cancer, and in two families with breast and/or ovarian cancer, one of which also carried a BRCA1 pathogenic variant (Li 2015, Easton 2016). BRIP1 Gln554Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glutamine and Glutamic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. BRIP1 Gln554Glu 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 Gln554Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590587 SCV000699673 uncertain significance not provided 2016-04-25 criteria provided, single submitter clinical testing Variant summary: The c.1660C>G variant affects a non-conserved nucleotide, resulting in amino acid change from Gln to Glu. 3/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). This variant is not found in 119888 control chromosomes. This variant has been reported in at least two BrC/OvC families and one of them also carried a potentially pathogenic variant in BRCA1 c.547+1G>T. The variant of interest has not, to our knowledge, been reported in affected individuals via reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the lack of clinical information and functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.

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.