ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7670C>T (p.Ala2557Val)

dbSNP: rs775219538
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767199 SCV000566553 uncertain significance not provided 2015-05-11 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7670C>T at the cDNA level, p.Ala2557Val (A2557V) at the protein level, and results in the change of an Alanine to a Valine (GCA>GTA). Using alternate nomenclature, this variant would be defined as BRCA2 7898C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ala2557Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ala2557Val occurs at a position that is conserved in mammals and is located within the DNA binding domain (Borg 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA2 Ala2557Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483370 SCV000600764 uncertain significance not specified 2016-12-05 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000773099 SCV000906560 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-03 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001048438 SCV001212444 uncertain significance Hereditary breast ovarian cancer syndrome 2024-10-01 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2557 of the BRCA2 protein (p.Ala2557Val). This variant is present in population databases (rs775219538, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer (PMID: 35918668). ClinVar contains an entry for this variant (Variation ID: 419030). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA2 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.
Center for Precision Medicine, Meizhou People's Hospital RCV002250635 SCV002520836 uncertain significance Familial cancer of breast no assertion criteria provided curation

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