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
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.
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
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.
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
Color RCV000116149 SCV000537546 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000855583 SCV000699705 uncertain significance not specified 2019-01-29 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.2830C>G (p.Gln944Glu) results in a conservative amino acid change located in the BRCA1 binding domain (Suhasini 2013) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 289526 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.0024 in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 38 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRIP1 causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Moreover, in the Japanese control population the variant was reported with an even higher allele frequency of (0.005), further supporting the benign nature of the variant (HGVD). The variant, c.2830C>G has also been reported in the literature in BRCA1/2 mutation-negative individuals, primarily of Asian descent, who were affected with breast cancer, including one publication which found the variant in two families, one of which showed partial co-segregation with disease (Cao 2009). However, in most of these reports no other cancer predisposition genes were genotyped, therefore these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact on protein function that indicate the variant could affect BRIP1 function (Nath 2017). Six other 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 VUS-possibly benign.
Mendelics RCV000411198 SCV000839363 uncertain significance Fanconi anemia, complementation group J 2018-07-02 criteria provided, single submitter clinical testing

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