Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV000580607 | SCV000682933 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-09-19 | criteria provided, single submitter | clinical testing | This missense variant replaces serine with threonine at codon 36 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). A functional study has shown that the variant protein is functional in a human haploid cell line-based survival assay (PMID: 30209399). This variant has not 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). 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 | RCV000637402 | SCV000758858 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2022-08-16 | criteria provided, single submitter | clinical testing | Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. 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: 25823446, 30209399). ClinVar contains an entry for this variant (Variation ID: 489704). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 36 of the BRCA1 protein (p.Ser36Thr). |
| ARUP Laboratories, |
RCV002227184 | SCV002506219 | uncertain significance | not provided | 2022-01-14 | criteria provided, single submitter | clinical testing | The BRCA1 c.106T>A; p.Ser36Thr variant (rs905812561), to our knowledge, is not reported in the medical literature associated with disease but is reported in ClinVar (Variation ID: 489704). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at codon 36 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.605). One in vitro functional study demonstrates no significant effect on homology-directed repair activity (Starita 2015). However, given the lack of clinical and functional data, the significance of the p.Ser36Thr variant is uncertain at this time. References: Starita LM et al. Massively Parallel Functional Analysis of BRCA1 RING Domain Variants. Genetics. 2015 Jun;200(2):413-22. PMID: 25823446. |
| Ambry Genetics | RCV000580607 | SCV002722794 | likely benign | Hereditary cancer-predisposing syndrome | 2023-02-23 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
| Brotman Baty Institute, |
RCV001076581 | SCV001242359 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro |