Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000218947 | SCV000278772 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-01-20 | criteria provided, single submitter | clinical testing | The p.G1366D variant (also known as c.4097G>A) is located in coding exon 10 of the BRCA1 gene. The glycine at codon 1366 is replaced by aspartic acid, an amino acid with similar properties. This change occurs in the first base pair of coding exon 10. In one functional study, normal mRNA splicing was observed for this alteration and sequence analysis of cDNA revealed bi-allelic expression of normal transcript (Colombo M et al. Science. PLoS One. 2013;8(2):e57173). This amino acid position is well conserved in available vertebrate species; however, aspartic acid is the reference amino acid in other 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 | RCV000803368 | SCV000943234 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-12-17 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1366 of the BRCA1 protein (p.Gly1366Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 234236). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Studies have shown that this missense change does not affect mRNA splicing (PMID: 23451180). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001420906 | SCV001623351 | uncertain significance | not specified | 2021-04-19 | criteria provided, single submitter | clinical testing | Variant summary: BRCA1 c.4097G>A (p.Gly1366Asp) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant also alters a conserved first coding nucleotide of exon 11 adjacent to the penultimate intronic canonical splice acceptor site. 4/4 computational tools predict no significant impact on normal splicing. An additional prediction protocol named splicing prediction in consensus elements (SPiCE) has also reported no impact on splicing (Leman_2018). Consistently, the variant was not reported to be associated with an impact on mRNA splicing using an in-vitro assay (Colombo_2013). The variant was absent in 247322 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4097G>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |