Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000222863 | SCV000274628 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-03-12 | criteria provided, single submitter | clinical testing | The p.R1076I variant (also known as c.3227G>T or 3346G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 3227. The arginine at codon 1076 is replaced by isoleucine, 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 of 6503 at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 105000 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 tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.R1076I remains unclear. |
| Invitae | RCV000543033 | SCV000635889 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2017-05-02 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 230930). This sequence change replaces arginine with isoleucine at codon 1076 of the BRCA1 protein (p.Arg1076Ile). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and isoleucine. 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: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. |
| University of Washington Department of Laboratory Medicine, |
RCV000222863 | SCV003850721 | likely benign | Hereditary cancer-predisposing syndrome | 2023-03-23 | criteria provided, single submitter | curation | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). |