Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001342449 | SCV001536382 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2022-02-25 | criteria provided, single submitter | clinical testing | 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. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 25056273). 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. ClinVar contains an entry for this variant (Variation ID: 54649). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 23961350). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 898 of the BRCA1 protein (p.Lys898Glu). |
| Ambry Genetics | RCV002426606 | SCV002743425 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-01-21 | criteria provided, single submitter | clinical testing | The p.K898E variant (also known as c.2692A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 2692. The lysine at codon 898 is replaced by glutamic acid, an amino acid with similar properties. In one study, this variant was detected in 1/134 non-Ashkenazi Jewish Argentinean breast and/or ovarian cancer patients. However, this patient was also found to carry an alteration in the BRCA2 gene that was considered deleterious (Solano AR et al. Springerplus, 2012 Sep;1:20). A functional study suggests this alteration may interfere with the interaction between BRCA1 and the PP1-binding motif which may impair DNA damage repair mechanisms (Chen BY et al. Sci Rep, 2014 Jul;4:5812). 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. |
| University of Washington Department of Laboratory Medicine, |
RCV002426606 | SCV003849420 | 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). |
| Color Diagnostics, |
RCV002426606 | SCV004360261 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-08-15 | criteria provided, single submitter | clinical testing | This missense variant replaces lysine with glutamic acid at codon 898 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant has been reported in an individual affected with breast or ovarian cancer who has an unspecified deleterious BRCA2 variant (PMID: 23961350) and in a breast cancer case-control meta-analysis in 0/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000636). A multifactorial analysis also has reported likelihood ratios for pathogenicity based on co-occurrence and family history of 1.0331 and 0.1078, respectively (PMID: 31131967). This variant has not been identified 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. |
| Breast Cancer Information Core |
RCV000111920 | SCV000144516 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2003-12-23 | no assertion criteria provided | clinical testing |