ClinVar Genomic variation as it relates to human health

Variant summary: BRCA2 c.8632G>A (p.Glu2878Lys) results in a conservative amino acid change located in the BRCA2, OB2 domain (IPR048262) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes/weakens the canonical 5' splicing donor site. Further, 2 independent clinical laboratories with established RNA assays reported that this variant causes skipping of exon 20 (NMD predicted) and/or aberrant splicing (Invitae, Ambry Genetics; ClinVar). The variant was absent in 250782 control chromosomes. c.8632G>A has been reported in the literature in the heterozygous state in multiple individuals affected with clinical features of Hereditary Breast And Ovarian Cancer Syndrome (example, Zhong_2016, Bhaskaran_2019, Gao_2020, Ercoskun_2022, DiRado_2023, Zhang_2022). These reports suggest the variant may be associated with BRCA2-related conditions. The following publications have been ascertained in the context of this evaluation (PMID: 30702160, 38136276, 35418818, 31825140, 35918668, 27257965). ClinVar contains an entry for this variant (Variation ID: 91730). Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2878 of the BRCA2 protein (p.Glu2878Lys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 27257965, 30702160, 35418818). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 91730). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 20 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

The c.8632G>A variant (also known as p.E2878K), located in coding exon 19 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8632. The amino acid change results in glutamic acid to lysine at codon 2878, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 19, which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported in the literature in several individuals from breast and ovarian cancer cohorts (Bhaskaran SP et al. Int J Cancer, 2019 08;145:962-973; Zhong X et al. PLoS One, 2016 Jun;11:e0156789; Ercoskun P et al. Mol Syndromol. 2022 Feb;13(2):123-131). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). As a missense alteration, this variant is predicted to be tolerated by protein in silico analysis and has been reported to be functional in a cDNA-based assay of homology-directed repair (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.