Submissions for variant NM_000059.4(BRCA2):c.3848T>C (p.Val1283Ala)

dbSNP: rs80358628

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000215042	SCV000279509	uncertain significance	not provided	2015-10-21	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.3848T>C at the cDNA level, p.Val1283Ala (V1283A) at the protein level, and results in the change of a Valine to an Alanine (GTA>GCA). Using alternate nomenclature, this variant has been previously published as BRCA2 4076T>C, having been observed in a case of contralateral breast cancer (Borg 2010). BRCA2 Val1283Ala 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 Valine and Alanine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Val1283Ala occurs at a position that is not conserved and is located in a region that interacts with RAD51 (Roy 2012). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Val1283Ala is pathogenic or benign.
Ambry Genetics	RCV000509623	SCV000607877	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-30	criteria provided, single submitter	clinical testing	The p.V1283A variant (also known as c.3848T>C), located in coding exon 10 of the BRCA2 gene, results from a T to C substitution at nucleotide position 3848. The valine at codon 1283 is replaced by alanine, an amino acid with similar properties. This amino acid position is poorly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854737	SCV002193580	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-07-07	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. 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. ClinVar contains an entry for this variant (Variation ID: 234575). 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 valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1283 of the BRCA2 protein (p.Val1283Ala).
University of Washington Department of Laboratory Medicine, University of Washington	RCV000509623	SCV003846915	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).