ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.3371A>G (p.Glu1124Gly) (rs1064793894)

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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 RCV000570953 SCV000666207 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000484914 SCV000567292 uncertain significance not provided 2017-02-15 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.3371A>G at the cDNA level, p.Glu1124Gly (E1124G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAA>GGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Glu1124Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Glu1124Gly occurs at a position that is not conserved and is not located in a known functional domain (Cantor 2011, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRIP1 Glu1124Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000701214 SCV000830004 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-02-26 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 1124 of the BRIP1 protein (p.Glu1124Gly). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 419472). 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.

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