ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.3758C>T (p.Ala1253Val)

dbSNP: rs730881527
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160070 SCV000210324 uncertain significance not provided 2014-04-03 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3758C>T at the cDNA level, p.Ala1253Val (A1253V) at the protein level, and results in the change of an Alanine to a Valine (GCA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ala1253Val 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 and is unlikely to affect protein integrity. BRCA2 Ala1253Val occurs at a position that is moderately conserved across species and is located in the RAD51 interaction region (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 Ala1253Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000238817 SCV000488679 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2016-05-23 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002298486 SCV002592806 uncertain significance Hereditary breast ovarian cancer syndrome 2022-08-20 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1253 of the BRCA2 protein (p.Ala1253Val). ClinVar contains an entry for this variant (Variation ID: 182204). 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. 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV003157429 SCV003846846 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).
Sharing Clinical Reports Project (SCRP) RCV000238817 SCV000297521 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2008-12-04 no assertion criteria provided clinical testing

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