Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000531377 | SCV000635934 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2017-03-02 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine with alanine at codon 1349 of the BRCA1 protein (p.Thr1349Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. 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. 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 alanine 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. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. |
Ambry Genetics | RCV001021742 | SCV001183393 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-01-23 | criteria provided, single submitter | clinical testing | The p.T1349A variant (also known as c.4045A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 4045. The threonine at codon 1349 is replaced by alanine, an amino acid with similar 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. |
University of Washington Department of Laboratory Medicine, |
RCV001021742 | SCV003850248 | 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). |