Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000214049 | SCV000273512 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-06-14 | criteria provided, single submitter | clinical testing | The p.S681R variant (also known as c.2043T>G), located in coding exon 9 of the BRCA1 gene, results from a T to G substitution at nucleotide position 2043. The serine at codon 681 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is poorly 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. |
| Invitae | RCV000542308 | SCV000635826 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2022-07-30 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 681 of the BRCA1 protein (p.Ser681Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 26287763). ClinVar contains an entry for this variant (Variation ID: 230089). 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. |
| Color Diagnostics, |
RCV000214049 | SCV000909355 | likely benign | Hereditary cancer-predisposing syndrome | 2017-04-26 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000779863 | SCV000916732 | uncertain significance | not specified | 2023-08-23 | criteria provided, single submitter | clinical testing | Variant summary: BRCA1 c.2043T>G (p.Ser681Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251312 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2043T>G has been reported in the literature in individuals affected with breast cancer (e.g. Pal_2015, Vidula_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26287763, 32571788). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments: two classified the variant as uncertain significance, and two classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| University of Washington Department of Laboratory Medicine, |
RCV000214049 | SCV003849548 | 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). |