BRCA2 NM_000059.4:c.7879A>T, Ile2627Phe

Variant summary: BRCA2 c.7879A>T (p.Ile2627Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251356 control chromosomes. c.7879A>T has been well reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer in literature spanning over ten years to include multifactorial probability models for assessing pathogenic outcomes (example, Borg_2010, Capanu_2011, Stegel_2011, Spitzer_2000, Kluska_2015, Couch_2015, Rebbeck_2018, Lindor_2012, Easton_2007). These data indicate that the variant is very likely to be associated with disease. At-least one co-occurrence with another pathogenic variant has been reported in a patient with triple negative breast cancer (PALB2 c.2470dupT, p.Cys824LeufsX2)(Couch_2015). However, this does not rule out the pathogenicity of this variant due to the possibility of mutual exclusivity of the two variants. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an inability to complement the lethality of mBRCA2-deficient mouse-embryonic stem (mES) cells (example, Hendriks_2014 and Mesman_2019) as well as decreased homology directed repair activity (example, Farrugia_2008, Guidguli_2012). One expert panel (ENIGMA) and ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Some submitters cite overlapping evidence utilized in the context of this evaluation. All submitters classified the variant as pathogenic (n=8)/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.

The p.I2627F variant (also known as c.7879A>T), located in coding exon 16 of the BRCA2 gene, results from an A to T substitution at nucleotide position 7879. The isoleucine at codon 2627 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been classified as pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Easton D et al. Am J Hum Genet. 2007;81:873-883; Vallee M et al. Hum Mutat. 2012 Jan;33(1):22-8; Lindor NM et al. Hum. Mutat. 2012;33(1):8-21; Hendriks G et al. Hum. Mutat. 2014;35(11):1382-91). In multiple studies, this alteration was detected in several individuals with breast or ovarian cancer (Spitzer E et al. Int. J. Cancer 2000;85(4):474-81; Balabas A et al. Fam. Cancer 2010;9(3):267-74; Stegel V et al. BMC Med. Genet. 2011;12():9; Kluska A et al. BMC Med Genomics 2015;8():19; Couch FJ et al. J. Clin. Oncol. 2015;33(4):304-11; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238; Zakrzewski F et al. BMC Cancer 2019 Apr;19(1):396). This alteration was identified in 1/150 unselected patients with recurrent or metastatic prostate cancer (Isaacsson Velho P et al. Prostate 2018 04;78:401-407). A homology-directed DNA repair (HDR) assay demonstrated p.I2627F to have low functionality, with a probability of pathogenicity of 0.990 (Guidugli L et al. Am. J. Hum. Genet. 2018 Feb;102(2):233-248). In another study, this variant was non-functional in a homology-directed DNA repair (HDR) assay (Hart SN et al. Genet Med. 2019 01;21:71-80). In addition, a mouse embryonic stem cell assay showed that p.I2627F was unable to complement Brca2-deficient cell lethal phenotype (Mesman R et al. Genet. Med. 2019 02;21(2):293-302). 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 addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

This missense variant replaces isoleucine with phenylalanine at codon 2627 in the DNA binding domain of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA2 function in homology-mediated repair and complementation of Brca2-deficient mouse embryonic stem cells (PMID: 18451181, 23108138, 29394989, 29988080, 33609447). This variant has been reported in over ten individuals affected with breast cancer (PMID: 10699917, 20104584, 20383589, 21520273, 29335924) and prostate cancer (PMID: 29368341). This variant also has been reported with a family history likelihood ratio for pathogenicity of 2.61 (PMID: 18451181), and it has been observed in six breast cancer-affected individuals of Macedonian origin, who showed significant family history of BRCA2-related cancers (PMID: 29335924). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2627 of the BRCA2 protein (p.Ile2627Phe). 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 and prostate cancer (PMID: 10699917, 20104584, 20383589, 21232165, 25452441, 29335924, 29368341). This variant is also known as 8107A>T. ClinVar contains an entry for this variant (Variation ID: 52430). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 18451181, 23108138, 25146914, 29394989, 29884841). For these reasons, this variant has been classified as Pathogenic.

In the published literature, the variant has been reported in individuals and families with breast cancer (PMID: 29335924 (2018), 25948282 (2015), 25452441 (2015), 21232165 (2011), 20104584 (2010), 18451181 (2008)), and it has been classified as pathogenic in multifactorial analysis studies (PMID: 17924331 (2007), 21990134 (2012)). Additional functional studies indicate the variant has deleterious effects on BRCA2 protein functions (PMID: 23108138 (2013), 29988080 (2018)). Based on the available information, this variant is classified as pathogenic.