Total submissions: 11
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000132266 | SCV000187349 | likely benign | Hereditary cancer-predisposing syndrome | 2020-09-14 | 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. |
Gene |
RCV000235134 | SCV000210205 | uncertain significance | not specified | 2016-08-21 | criteria provided, single submitter | clinical testing | This variant is denoted BRCA1 c.5189A>G at the cDNA level, p.Asn1730Ser (N1730S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). Using alternate nomenclature, this variant would be defined as BRCA1 5308A>G. Lee et al. (2010) concluded that BRCA1 Asn1730Ser behaved similar to wild type on in vitro assays interrogating transcription, stability, and binding. BRCA1 Asn1730Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Asn1730Ser occurs at a position that is not conserved and is located within the BRCT 1 domain and a region known to interact with multiple other proteins (Paul 2014, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Asn1730Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
Counsyl | RCV000077607 | SCV000488026 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2015-12-28 | criteria provided, single submitter | clinical testing | |
Department of Pathology and Molecular Medicine, |
RCV000235134 | SCV000588062 | benign | not specified | 2017-04-20 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000985247 | SCV000605907 | likely benign | not provided | 2023-03-31 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000132266 | SCV000905816 | benign | Hereditary cancer-predisposing syndrome | 2015-11-16 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000235134 | SCV000916820 | likely benign | not specified | 2022-08-01 | criteria provided, single submitter | clinical testing | Variant summary: BRCA1 c.5189A>G (p.Asn1730Ser) results in a conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. In addition, this variant has been classified as likely benign based on the amount of available evidence and/or prior likelihood of pathogenicity based on variant location and predicted effect (Cline_2019), and this variant was also predicted as neutral by different prediction tools (CAGI class: 2, Padilla_2019). The variant allele was found at a frequency of 2e-05 in 251130 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5189A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Pavlicek_2004, Chen_2006). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. The variant was shown to have no protein folding defect, normal peptide binding activity and specificity, and normal transcriptional activity (Lee_2010, Findlay__2018, Fernandes_2019). Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3), likely benign (n=2) and benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. |
Invitae | RCV001305771 | SCV001495118 | likely benign | Hereditary breast ovarian cancer syndrome | 2024-01-18 | criteria provided, single submitter | clinical testing | |
Sharing Clinical Reports Project |
RCV000077607 | SCV000109410 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2010-11-17 | no assertion criteria provided | clinical testing | |
Breast Cancer Information Core |
RCV000077607 | SCV000145375 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2002-05-29 | no assertion criteria provided | clinical testing | |
Brotman Baty Institute, |
RCV000077607 | SCV001237836 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro |