Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000214355 | SCV000272994 | uncertain significance | Hereditary cancer-predisposing syndrome | 2014-11-25 | criteria provided, single submitter | clinical testing | The p.E671G variant (also known as c.2012A>G), located in coding exon 13 of the BRIP1 gene, results from an A to G substitution at nucleotide position 2012. The glutamic acid at codon 671 is replaced by glycine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.005% (greater than 22000 alleles tested) in our clinical cohort. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be benign and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.E671G remains unclear. |
| Gene |
RCV000767211 | SCV000279823 | uncertain significance | not provided | 2016-01-22 | criteria provided, single submitter | clinical testing | This variant is denoted BRIP1 c.2012A>G at the cDNA level, p.Glu671Gly (E671G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAG>GGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Glu671Gly 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 Glu671Gly occurs at a position that is not conserved and is located in the helicase domain (Cantor 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRIP1 Glu671Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Invitae | RCV000636172 | SCV000757604 | uncertain significance | Familial cancer of breast; Fanconi anemia, complementation group J | 2019-10-01 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid with glycine at codon 671 of the BRIP1 protein (p.Glu671Gly). The glutamic acid residue is moderately 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: 133750). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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. |
| Color | RCV000214355 | SCV001341600 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-12-05 | criteria provided, single submitter | clinical testing | |
| ITMI | RCV000120394 | SCV000084546 | not provided | not specified | 2013-09-19 | no assertion provided | reference population |