ClinVar

Description

The BRCA2 p.His1256Pro variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, LOVD 3.0, ARUP Laboratories, Zhejiang University 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). The variant was identified in dbSNP (ID: rs80358618) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry genetics, BIC), UMD-LSDB (2x as unclassified variant), and in BIC Database (1x unknown significance). The p.His1256 residue is not conserved in mammals and four out of five 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 a variant of uncertain significance.