Submissions for variant NM_000059.4(BRCA2):c.7910C>T (p.Ala2637Val)

dbSNP: rs730881561

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160145	SCV000210451	uncertain significance	not provided	2014-06-05	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.7910C>T at the cDNA level, p.Ala2637Val (A2637V) at the protein level, and results in the change of an Alanine to a Valine (GCC>GTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ala2637Val 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 Ala2637Val occurs at a position that is highly variable across species and is located in the DNA-binding domain (Borg 2010). In addition, in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Ala2637Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV002415700	SCV002677014	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-16	criteria provided, single submitter	clinical testing	The p.A2637V variant (also known as c.7910C>T), located in coding exon 16 of the BRCA2 gene, results from a C to T substitution at nucleotide position 7910. The alanine at codon 2637 is replaced by valine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002515112	SCV003302072	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-25	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 2637 of the BRCA2 protein (p.Ala2637Val). 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: 182246). 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.
Baylor Genetics	RCV003462079	SCV004213679	uncertain significance	Familial cancer of breast	2023-08-11	criteria provided, single submitter	clinical testing