ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3464G>A (p.Gly1155Glu) (rs45603843)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000116158 SCV000217675 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000116158 SCV000689380 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Counsyl RCV000662581 SCV000785202 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-06-01 criteria provided, single submitter clinical testing
GeneDx RCV000662347 SCV000150067 uncertain significance not provided 2016-04-03 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.3464G>A at the cDNA level, p.Gly1155Glu (G1155E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGA>GAA). This variant has been observed in at least two women with breast cancer; however, segregation analysis in one of these individual's family showed that this variant did not segregate with disease (Lewis 2005, Tung 2016). BRIP1 Gly1155Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glycine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Gly1155Glu occurs at a position that is not conserved and is not located in a known functional domain (Cantor 2011, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRIP1 Gly1155Glu is pathogenic or benign. We consider it to be a variant of uncertain significance.
GenomeConnect, ClinGen RCV000662347 SCV000784715 not provided not provided no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Invitae RCV000200049 SCV000255172 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-07-09 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 1155 of the BRIP1 protein (p.Gly1155Glu). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family and two independent individuals affected with breast cancer (PMID: 16280053, 26976419, 27997549). However, it did not segregate with disease in the family analyzed. It was inherited from the paternal side of the family with no history of breast cancer, and was not present in the maternal side of the family in 4 affected individuals (PMID: 16280053). ClinVar contains an entry for this variant (Variation ID: 128189). 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.

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