ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3444C>A (p.Asp1148Glu) (rs28997573)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131003 SCV000185928 likely benign Hereditary cancer-predisposing syndrome 2018-01-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,Other data supporting benign classification,In silico models in agreement (benign)
Color RCV000131003 SCV000902753 likely benign Hereditary cancer-predisposing syndrome 2016-06-06 criteria provided, single submitter clinical testing
Counsyl RCV000411479 SCV000490063 uncertain significance Fanconi anemia, complementation group J 2016-11-02 criteria provided, single submitter clinical testing
Counsyl RCV000409042 SCV000490064 uncertain significance Neoplasm of ovary 2016-11-02 criteria provided, single submitter clinical testing
GeneDx RCV000589005 SCV000210829 uncertain significance not provided 2018-09-19 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.3444C>A at the cDNA level, p.Asp1148Glu (D1148E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAC>GAA). Although this variant has been reported in individuals with breast, ovarian, or Lynch syndrome-associated cancers and/or colon polyps, it has also been observed in healthy controls (Ramus 2015, Yurgelun 2015, Easton 2016). In addition, BRIP1 Asp1148Glu was identified in 1/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014); of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. BRIP1 Asp1148Glu was observed at an allele frequency of 0.02% (26/126,468) in individuals of European ancestry 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 Asp1148Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000120402 SCV000084554 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000589005 SCV000699724 uncertain significance not provided 2017-01-26 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.3444C>A (p.Asp1148Glu) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a benign outcome for this variant . This variant was found in 15/131898 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000165 (11/66494). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The varaint was reported in the literature in BrC/OvC patients, without strong evidence for causality, as well as in a Lynch syndrome patient who carried a potentially pathogenic MLH1 variant (c.1989+3dupC; Yurgelun_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as a VUS, while one classified it as likely benign. Due to the relatively high frequency of the variant in the general population, multiple in silico tools predict benign outcome, as well as the co-occurrence in a patient with a potentially pathogenic variant, this variant has been classified as possibly benign variant until additional evidence becomes available.
Invitae RCV000204453 SCV000260424 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-01-01 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 1148 of the BRIP1 protein (p.Asp1148Glu). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs28997573, ExAC 0.02%). This variant has been reported in individuals with suspected Lynch syndrome, ovarian cancer, breast cancer and renal clear cell carcinoma (PMID: 25980754, 26315354, 25186627, 26689913), as well as unaffected control individuals (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 133758). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Mendelics RCV000411479 SCV000839349 uncertain significance Fanconi anemia, complementation group J 2018-07-02 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000131003 SCV000787968 likely benign Hereditary cancer-predisposing syndrome 2017-10-30 no assertion criteria provided clinical testing

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.