Submissions for variant NM_000059.4(BRCA2):c.7477A>G (p.Met2493Val)

dbSNP: rs1064793329

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482631	SCV000565820	uncertain significance	not provided	2016-09-12	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.7477A>G at the cDNA level, p.Met2493Val (M2493V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). Using alternate nomenclature, this variant would be defined as BRCA2 7705A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Met2493Val 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 Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Met2493Val occurs at a position that is not conserved and is located in the DNA binding domain and the FANCD2 binding domain (Yang 2002, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Met2493Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005090927	SCV005810111	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-03-11	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2493 of the BRCA2 protein (p.Met2493Val). This variant is not present in population databases (gnomAD no frequency). 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: 418623). 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.