ClinVar

Description

The BRCA2 p.Gln347Arg variant was identified in dbSNP (ID: rs55800493) “With likely benign, other allele”, with a minor allele frequency of 0.0024 (1000 Genomes Project), Clinvitae database, the ClinVar database (classified as a “likely benign” by Invitae, Ambry Genetics, GeneDx, Emory Genetics Laboratory and Sharing Clinical Reports Project), the BIC database (9X with unknown clinical importance), and UMD (2X as an unknown variant). This variant was also identified in the Exome Variant Server project in 17 of 4400 European American alleles, and the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 45 of 9928 chromosomes (frequency: 0.0045) from a population of African individuals. The variant was also found at low frequencies in Latino (8.66E-05) and European (Non-Finnish) individuals (1.51E-05), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Gln347 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as likely benign.