ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3507C>A (p.Asp1169Glu) (rs375741316)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216628 SCV000278299 uncertain significance Hereditary cancer-predisposing syndrome 2015-09-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
GeneDx RCV000255184 SCV000321487 uncertain significance not provided 2016-03-30 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.3507C>A at the cDNA level, p.Asp1169Glu (D1169E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAC>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Asp1169Glu was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Aspartic Acid and Glutamic Acid share similar properties, this is considered a conservative amino acid substitution. BRIP1 Asp1169Glu 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 Asp1169Glu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000205088 SCV000260641 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 1169 of the BRIP1 protein (p.Asp1169Glu). 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 (rs375741316, ExAC 0.002%). This variant has been reported in individuals affected with breast cancer (PMID: 26921362). ClinVar contains an entry for this variant (Variation ID: 220245). 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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