ClinVar

Description

The BRCA2 p.Arg3007Gly variant was identified in 1 of 164 proband chromosomes (frequency: 0.006) from French-Canadian individuals or families with hereditary breast cancer; (Cavallone 2010). In this study, the variant did not appear to segregate with disease in the affected family (and DNA was unavailable for further studies). The variant was also identified in dbSNP (ID: rs397507417) “With Uncertain significance allele”, ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, SCRP (Sharing Clinical Reports Project), and Dept. of Pathology and Molecular Medicine (Queen's University)), Clinvitae (4x), Genesight-COGR (4 clinical labs), LOVD 3.0 (1x), and UMD-LSDB (2x as 3-UV) and was not identified in Cosmic, MutDB, BIC Database, ARUP Laboratories, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017) databases. The variant was identified by our laboratory in 1 individual with breast cancer. The p.Arg3007 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Gly variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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 a variant of uncertain significance.