Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV000580356 | SCV000683153 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-03-17 | criteria provided, single submitter | clinical testing | This missense variant replaces serine with arginine at codon 1377 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a breast cancer case-control meta-analysis in 1/53460 unaffected individuals and absent in 60466 cases (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_006276). This variant has been identified in 2/248932 chromosomes 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 | RCV001363127 | SCV001559226 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-03-07 | criteria provided, single submitter | clinical testing | 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 not expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 55110). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 10923033). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 1377 of the BRCA1 protein (p.Ser1377Arg). 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. |
| Ambry Genetics | RCV000580356 | SCV004058395 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-06-20 | criteria provided, single submitter | clinical testing | The p.S1377R variant (also known as c.4131C>A), located in coding exon 10 of the BRCA1 gene, results from a C to A substitution at nucleotide position 4131. The serine at codon 1377 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported as a germline finding in a patient with ovarian cancer (Cunningham JM et al. Sci Rep, 2014 Feb;4:4026). 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. |
| Breast Cancer Information Core |
RCV000112268 | SCV000144994 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2002-05-29 | no assertion criteria provided | clinical testing |