Submissions for variant NM_000059.4(BRCA2):c.3922G>C (p.Glu1308Gln)

dbSNP: rs80358638

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001948557	SCV002203570	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-03-03	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 glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 1308 of the BRCA2 protein (p.Glu1308Gln). 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: 1431220).
Ambry Genetics	RCV002370551	SCV002623736	uncertain significance	Hereditary cancer-predisposing syndrome	2015-10-13	criteria provided, single submitter	clinical testing	The p.E1308Q variant (also known as c.3922G>C), located in coding exon 10 of the BRCA2 gene, results from a G to C substitution at nucleotide position 3922. The glutamic acid at codon 1308 is replaced by glutamine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6400 samples (12800 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 150000 alleles tested) in our clinical cohort. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.E1308Q remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002370551	SCV003848533	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).