Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000572449 | SCV000668420 | uncertain significance | Hereditary cancer-predisposing syndrome | 2016-06-06 | criteria provided, single submitter | clinical testing | The p.K307E variant (also known as c.919A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 919. The lysine at codon 307 is replaced by glutamic acid, an amino acid with similar properties. This alteration was detected in 10/92 breast and/or ovarian cancer families from mainland China and was noted to be the most common variant in BRCA1 found in this cohort (Kim YC et al. Oncotarget. 2016 Feb 23;7(8):9600-12). 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 0.0003% (greater than 300000 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 this alteration remains unclear. |
Color Diagnostics, |
RCV000572449 | SCV000683376 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-04-18 | criteria provided, single submitter | clinical testing | This missense variant replaces lysine with glutamic acid at codon 307 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial breast and/or ovarian cancer (PMID: 26848529). In a large breast cancer case-control study, this variant has been observed in 0/60466 cases and 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 2/251354 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Invitae | RCV000691850 | SCV000819646 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-10-08 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 307 of the BRCA1 protein (p.Lys307Glu). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 26848529, 30702160). ClinVar contains an entry for this variant (Variation ID: 482907). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. 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. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000758853 | SCV000887740 | uncertain significance | not provided | 2018-04-27 | criteria provided, single submitter | clinical testing | |
University of Washington Department of Laboratory Medicine, |
RCV000572449 | SCV003846291 | 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). |