Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000759535 | SCV000888909 | uncertain significance | not provided | 2018-03-20 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV001022025 | SCV001183713 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-03-09 | criteria provided, single submitter | clinical testing | The p.M1400T variant (also known as c.4199T>C), located in coding exon 11 of the BRCA1 gene, results from a T to C substitution at nucleotide position 4199. The methionine at codon 1400 is replaced by threonine, an amino acid with similar properties. This amino acid position is well 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. |
| Color Diagnostics, |
RCV001022025 | SCV001354034 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-08-08 | criteria provided, single submitter | clinical testing | This missense variant replaces methionine with threonine at codon 1400 of the BRCA1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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 | RCV001344408 | SCV001538460 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-08-03 | criteria provided, single submitter | clinical testing | 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. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 28781887, 30765603). 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 expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 55138). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 21520333). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1400 of the BRCA1 protein (p.Met1400Thr). |
| ARUP Laboratories, |
RCV000759535 | SCV002048919 | uncertain significance | not provided | 2021-04-23 | criteria provided, single submitter | clinical testing | The BRCA1 c.4199T>C; p.Met1400Thr variant (rs80357473), to our knowledge, is not reported in the medical literature in association with disease but is reported in ClinVar (Variation ID: 55138). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The methionine at codon 1400 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.276). Functional analyses of the variant protein show no significant effect on protein function (Woods 2016). Due to limited information, the clinical significance of the p.Met1400Thr variant is uncertain at this time. References: Woods NT et al. Functional assays provide a robust tool for the clinical annotation of genetic variants of uncertain significance. NPJ Genom Med. 2016;1:16001. PMID: 28781887. |
| Breast Cancer Information Core |
RCV000112294 | SCV000145026 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2003-12-23 | no assertion criteria provided | clinical testing |