Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000160000 | SCV000210204 | uncertain significance | not provided | 2014-05-16 | criteria provided, single submitter | clinical testing | This variant is denoted BRCA1 c.5186T>A at the cDNA level, p.Leu1729Gln (L1729Q) at the protein level, and results in the change of a Leucine to a Glutamine (CTG>CAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Leu1729Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Glutamine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Leu1729Gln occurs at a position that is well conserved among mammals and is located in in the BRCT 1 domain (UniProt). In addition, in silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider BRCA1 Leu1729Gln to be a variant of uncertain significance.Of note, two deleterious BRCA1 variants on opposite chromosomes (in trans) are expected to be incompatible with life. Therefore, if this variant is in trans with the pathogenic BRCA1 variant, then this variant is likely a polymorphism. Parental or family testing could help determine whether the variant is in cis or trans with the BRCA1 variant. |
| Ambry Genetics | RCV000165263 | SCV000215979 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-08-25 | criteria provided, single submitter | clinical testing | The p.L1729Q variant (also known as c.5186T>A), located in coding exon 17 of the BRCA1 gene, results from a T to A substitution at nucleotide position 5186. The leucine at codon 1729 is replaced by glutamine, an amino acid with dissimilar properties. One functional study found the significance of this nucleotide substitution to be uncertain in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Counsyl | RCV000411989 | SCV000488798 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2016-06-21 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001223270 | SCV001395410 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2024-01-07 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 1729 of the BRCA1 protein (p.Leu1729Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer, malignant melanoma, and/or ovarian cancer (PMID: 33067490, 34449592). This variant is also known as c.5249T>A (p.Leu1750Gln). ClinVar contains an entry for this variant (Variation ID: 182166). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 30209399). 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. |
| Baylor Genetics | RCV000411989 | SCV004215109 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2023-06-02 | criteria provided, single submitter | clinical testing | |
| Brotman Baty Institute, |
RCV000411989 | SCV001242800 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro |