Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000130420 | SCV000185283 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-08-03 | criteria provided, single submitter | clinical testing | The p.D1578G variant (also known as c.4733A>G), located in coding exon 14 of the BRCA1 gene, results from an A to G substitution at nucleotide position 4733. The aspartic acid at codon 1578 is replaced by glycine, an amino acid with similar properties. This alteration has been previously identified in one individual from a Hispanic breast and/or ovarian cancer cohort (Weitzel JN et al. Cancer Epidemiol. Biomarkers Prev., 2005 Jul;14:1666-71). 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. |
| Mendelics | RCV000709467 | SCV000839227 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2018-07-02 | criteria provided, single submitter | clinical testing | |
| Mendelics | RCV000112391 | SCV001140511 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Color Diagnostics, |
RCV000130420 | SCV001352664 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-11-13 | criteria provided, single submitter | clinical testing | This missense variant replaces aspartic acid with glycine at codon 1578 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one suspected hereditary breast and ovarian cancer family (PMID: 16030099) and a multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.0331 and 0.4825, 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. |
| Invitae | RCV000709467 | SCV001563506 | likely benign | Hereditary breast ovarian cancer syndrome | 2023-10-16 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001731345 | SCV001983632 | likely benign | not specified | 2021-09-19 | criteria provided, single submitter | clinical testing | Variant summary: BRCA1 c.4733A>G (p.Asp1578Gly) 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. A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as likely benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Cline_2019, Padilla_2019). The variant was absent in 251314 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4733A>G has been reported in the literature as a VUS in at-least one individual with a personal or family history of breast and/ or ovarian cancer (example, Weitzel_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in a transcriptional activation (TA) assay to determine the functional impact of missense variants coupled with VarCall, a Bayesian hierarchical model to estimate the likelihood of pathogenicity given the functional data (Woods_2016). Furthermore, multifactorial probability models predict a likely benign (IARC class 2) outcome (example, Parsons_2019). Five 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. Some submitters cite overlapping but not all the evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. |
| Baylor Genetics | RCV000112391 | SCV004215111 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2023-05-31 | criteria provided, single submitter | clinical testing | |
| Breast Cancer Information Core |
RCV000112391 | SCV000145169 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2003-12-23 | no assertion criteria provided | clinical testing |