Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000218490 | SCV000273273 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-01-10 | criteria provided, single submitter | clinical testing | The p.Q1562P variant (also known as c.4685A>C), located in coding exon 10 of the BRCA2 gene, results from an A to C substitution at nucleotide position 4685. The glutamine at codon 1562 is replaced by proline, an amino acid with similar properties. This alteration was identified in a cohort of 481 Chinese breast cancer patients with family history of breast/ovarian cancer (Wang J et al. Cancer Med, 2019 May;8:2074-2084). 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. |
Gene |
RCV000483116 | SCV000564781 | uncertain significance | not provided | 2015-02-19 | criteria provided, single submitter | clinical testing | This variant is denoted BRCA2 c.4685A>C at the cDNA level, p.Gln1562Pro (Q1562P) at the protein level, and results in the change of a Glutamine to a Proline (CAA>CCA). Using alternate nomenclature, this variant would be defined as BRCA2 4913A>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gln1562Pro was not observed at a significant allele frequency in 1000 Genomes. Since Glutamine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Gln1562Pro occurs at a position that is moderately conserved across species and is located in the RAD51 binding motif (Roy 2012). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Gln1562Pro is pathogenic or benign. We consider it to be a variant of uncertain significance. |
Invitae | RCV000697106 | SCV000825700 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-11-10 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1562 of the BRCA2 protein (p.Gln1562Pro). This variant is present in population databases (rs544688816, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 229904). 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 BRCA2 protein function with a negative predictive value of 95%. 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. |
Color Diagnostics, |
RCV000218490 | SCV000906087 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-06-09 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamine with proline at codon 1562 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251086 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. |
University of Washington Department of Laboratory Medicine, |
RCV000218490 | SCV003852017 | likely benign | Hereditary cancer-predisposing syndrome | 2023-03-23 | criteria provided, single submitter | curation | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). |
MGZ Medical Genetics Center | RCV003607260 | SCV004543894 | likely benign | Familial cancer of breast | 2024-02-09 | criteria provided, single submitter | clinical testing | ACMG codes applied following ENIGMA VCEP rules: BP1_STR |