ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2830C>G (p.Gln944Glu) (rs140233356)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000116149 SCV000214613 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000116149 SCV000537546 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-23 criteria provided, single submitter clinical testing
Counsyl RCV000411198 SCV000489957 uncertain significance Fanconi anemia, complementation group J 2016-08-23 criteria provided, single submitter clinical testing
Counsyl RCV000409338 SCV000489958 uncertain significance Neoplasm of ovary 2016-08-23 criteria provided, single submitter clinical testing
GeneDx RCV000585934 SCV000150058 uncertain significance not provided 2018-08-21 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.2830C>G at the cDNA level, p.Gln944Glu (Q944E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAG>GAG). This variant has been observed in several breast cancer patients, two of whom also had a family history of breast cancer (Cao 2009, Kim 2016, Easton 2016, Tung 2016, Sato 2017). BRIP1 Gln944Glu was observed at an allele frequency of 0.2% (46/18868) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located within the BRCA1 binding domain (Cantor 2011). 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 Gln944Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000585934 SCV000699705 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.2830C>G (p.Gln944Glu) variant located in the BRCA1 binding domain involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a benign outcome. This variant was found in 33/128198 control chromosomes including large and broad populations from ExAC, predominantly observed in the East Asian subpopulation at a frequency of 0.002311 (20/8654). This frequency is about 37 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 East Asian origin. However, multiple publications report this variant in breast cancer patients/families, primarily of Asian descent including one publication (Cao_2009) which found the variant two families, one of which showed partial cosegregation with disease as it was found in proband and her two affected maternal relatives. Another large case-control study reported the variant in one breast cancer patient but not in controls (Easton_2016). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. Therefore, until additional studies become available, in particular, functional studies, the variant of interest has been classified as a "Variant of Uncertain Significance - Possibly Benign."
Invitae RCV000199089 SCV000255163 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 944 of the BRIP1 protein (p.Gln944Glu). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is present in population databases (rs140233356, ExAC 0.2%). This variant has been reported in individuals affected with breast cancer, along with affected and unaffected family members (PMID: 18483852, 26790966, 26976419). ClinVar contains an entry for this variant (Variation ID: 128180). Experimental studies have shown that this missense change disrupts interaction with BRCA1, therefore affecting BRIP1 protein function (PMID: 28911102). 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 RCV000411198 SCV000839363 uncertain significance Fanconi anemia, complementation group J 2018-07-02 criteria provided, single submitter clinical testing

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