BRCA2 NM_000059.3:c.8023A>G, Ile2675Val

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Variant summary: BRCA2 c.8023A>G (p.Ile2675Val) results in a conservative amino acid change located in the BRCA2, OB1 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict that the variant creates a cryptic exonic 5-prime donor site. These predictions were confirmed by experimental evidence which demonstrated that the variant results in loss of a stretch of 309 nucleotides at the 3-prime terminal of exon 18 from the mRNA. Multiple studies observed abundant aberrant product and a complete absence of wild type product (Fraile-Bethencourt_2017, Houdayer_2012, Bonnet_2008). The variant allele was found at a frequency of 4e-06 in 251076 control chromosomes. c.8023A>G has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Rebbeck_2018, Hirotsu_2015, Blay_2013, Bonnet_2008, Palma_2008). These data indicate that the variant is very likely to be associated with disease. Six other ClinVar submitters (evaluation after 2014), including two expert panels, have cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This variant has been reported in healthy controls and in individuals affected with breast or ovarian cancer in the published literature (PMID: 30652428 (2019), 30287823 (2018), 29907814 (2018), 29383094 (2017), 28993434 (2018)). Additionally, functional studies indicate that this variant interferes with normal BRCA2 mRNA splicing (PMID: 28339459 (2017), 22505045 (2012), 18424508 (2008)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is disease causing and damaging. Variant is located in potentially critical domain of the protein. Therefore, the variant is classified as pathogenic.