Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000478837 | SCV000572242 | uncertain significance | not provided | 2016-11-07 | criteria provided, single submitter | clinical testing | This variant is denoted BRCA1 c.4910C>A at the cDNA level, p.Pro1637Gln (P1637Q) at the protein level, and results in the change of a Proline to a Glutamine (CCA>CAA). Using alternate nomenclature, this variant would be defined as BRCA1 5029C>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Pro1637Gln 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 Proline and Glutamine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Pro1637Gln occurs at a position that is not conserved and is located within a region known to interact with multiple proteins (Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Pro1637Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
Invitae | RCV001039099 | SCV001202611 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2022-05-06 | 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: 30209399). 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: 422707). 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 proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 1637 of the BRCA1 protein (p.Pro1637Gln). |
Ambry Genetics | RCV002350073 | SCV002646099 | likely benign | Hereditary cancer-predisposing syndrome | 2021-08-26 | 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, |
RCV001073141 | SCV001238645 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro |