ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3331G>C (p.Glu1111Gln) (rs587780248)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000116155 SCV000150064 uncertain significance not provided 2018-09-21 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.3331G>C at the cDNA level, p.Glu1111Gln (E1111Q) at the protein level, and results in the change of a Glutamic Acid to a Glutamine (GAA>CAA). This variant was observed in at least two individuals, one with breast and the other with ovarian cancer (Lu 2015, Ramus 2015). BRIP1 Glu1111Gln 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 Glu1111Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000204181 SCV000259653 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-09-25 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 1111 of the BRIP1 protein (p.Glu1111Gln). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs587780248, ExAC 0.003%). This variant has been reported in individuals affected with ovarian and breast cancer (PMID: 26315354, 26689913). ClinVar contains an entry for this variant (Variation ID: 128186). 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"). 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.
Ambry Genetics RCV000214821 SCV000273518 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-13 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000409119 SCV000490027 uncertain significance Fanconi anemia, complementation group J 2016-10-05 criteria provided, single submitter clinical testing
Counsyl RCV000410336 SCV000490028 uncertain significance Neoplasm of ovary 2016-10-05 criteria provided, single submitter clinical testing
Color RCV000214821 SCV000684257 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001194197 SCV001363544 uncertain significance not specified 2019-03-07 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.3331G>C (p.Glu1111Gln) results in a conservative amino acid change in 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 1.8e-05 in 276776 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. This variant has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Lu_2015, Ramus_2015). These reports do 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. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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