Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000204756 | SCV000262417 | uncertain significance | Hereditary breast and ovarian cancer syndrome | 2019-12-16 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid with glycine at codon 747 of the BRCA2 protein (p.Glu747Gly). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs397507283, ExAC 0.03%). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 37778). 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 glycine 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. |
Ambry Genetics | RCV000215823 | SCV000277257 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-03-30 | criteria provided, single submitter | clinical testing | The p.E747G variant (also known as c.2240A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 2240. The glutamic acid at codon 747 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Gene |
RCV000657147 | SCV000571741 | uncertain significance | not provided | 2018-02-13 | criteria provided, single submitter | clinical testing | This variant is denoted BRCA2 c.2240A>G at the cDNA level, p.Glu747Gly (E747G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAA>GGA). Using alternate nomenclature, this variant would be defined as BRCA2 2468A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Glu747Gly 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 a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Glu747Gly is pathogenic or benign. We consider it to be a variant of uncertain significance. |
Department of Pathology and Laboratory Medicine, |
RCV000487003 | SCV000591796 | uncertain significance | not specified | 2014-09-10 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000487003 | SCV000600505 | uncertain significance | not specified | 2017-05-24 | criteria provided, single submitter | clinical testing | |
Color Health, |
RCV000215823 | SCV000903248 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-12-05 | criteria provided, single submitter | clinical testing | |
Integrated Genetics/Laboratory Corporation of America | RCV000487003 | SCV000918823 | uncertain significance | not specified | 2017-11-06 | criteria provided, single submitter | clinical testing | Variant summary: The BRCA2 c.2240A>G (p.Glu747Gly) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant, however these predictions have yet to be confirmed by functional studies. This variant was found in 9/246080 control chromosomes at a frequency of 0.0000366, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases; nor evaluated for functional impact by in vivo/vitro studies. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. |
Illumina Clinical Services Laboratory, |
RCV001112185 | SCV001269825 | uncertain significance | Fanconi anemia, complementation group D1 | 2018-01-13 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |
Illumina Clinical Services Laboratory, |
RCV000031359 | SCV001269826 | uncertain significance | Breast-ovarian cancer, familial 2 | 2018-01-13 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |
Sharing Clinical Reports Project |
RCV000031359 | SCV000053964 | uncertain significance | Breast-ovarian cancer, familial 2 | 2010-07-30 | no assertion criteria provided | clinical testing |