ClinVar

Description

The BRCA2 p.Ile481Val variant was not identified in the literature nor was it identified in the GeneInsight-COGR, Cosmic, MutDB, BIC Database, ARUP Laboratories, Zhejiang Colon Cancer Database, databases. The variant was identified in dbSNP (ID: rs760559435) as “With Uncertain significance”, in ClinVar (1x, as uncertain significance, by Invitae), Clinvitae (1x, as uncertain significance), LOVD 3.0 (2x), UMD-LSDB (1x record, as 3-UV), databases. The variant was also identified in control databases in 1 of 239798 chromosomes at a frequency of 0.000004 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Ile481 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 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. The variant is located with the Breast cancer type 2 susceptibility protein functional domain(s) increasing the likelihood that it may have clinical significance. 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.