ClinVar

Description

Variant summary: BRCA2 c.8954-5_8954-2delAACA alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 281868 control chromosomes, predominantly at a frequency of 0.0015 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.8954-5_8954-2delAACA, has been reported in the literature in individuals affected with breast cancer but without evidence for causality (Carney_2010, Chan_2018, Lai_2017, Suter_2004). In addition, co-occurrences with pathogenic BRCA2 variant have been reported (c.7878G>A, p.Trp2626X; Carney_2010, LabCorp internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS (n=2), Benign (n=2)). Based on the evidence outlined above, the variant was classified as benign.