ClinVar Genomic variation as it relates to human health

Variant summary: BRCA2 c.8755-19A>G alters a non-conserved nucleotide located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates an additional intronic 3' acceptor site before the canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 249352 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8755-19A>G has been reported in the literature without strong evidence for causality in at least three individuals affected with breast cancer undergoing BRCA1/2 testing, either due to a positive family history, an early disease onset, and/or categorization as high risk as per NCCN guidelines (e.g. Torres_2017, Abdel-Razeq_2021, Abdel-Razeq_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35402282, 34290354, 32467295, 28680148). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments, classifying the variant as either VUS (n=4) or likely benign (n=3). We have not ascertained any evidence supporting a pathogenic outcome for this variant in over five years since its initial observation at our laboratory. Based on the evidence outlined above, the variant was classified as likely benign.

The BRCA2 c.8755-19A>G variant (rs398122713) is reported in the literature in at least one individual affected with breast cancer (Torres 2017). This variant is also reported in ClinVar (Variation ID: 91734), and is only observed on six alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical acceptor splice site and creating a novel cryptic acceptor splice site. However, without functional studies the effect on splicing is unknown. Due to limited information, the clinical significance of the c.8755-19A>G variant is uncertain at this time. References: Torres et al. Prevalence and Penetrance of BRCA1 and BRCA2 Germline Mutations in Colombian Breast Cancer Patients. Sci Rep. 2017 Jul 5;7(1):4713.

This variant is denoted BRCA2 c.8755-19A>G or IVS21-19A>G and consists of a A>G nucleotide substitution at the -19 position of intron 21 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 8983-19A>G. Multiple in silico models predict that this variant results in the gain of a cryptic splice acceptor site upstream of the natural splice acceptor site, possibly leading to abnormal gene splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 c.8755-19A>G was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). The adenine (A) nucleotide that is altered is not conserved. Based on currently available evidence, it is unclear whether BRCA2 c.8755-19A>G is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.