Description
This variant is denoted BRCA2 c.7879A>T at the cDNA level, p.Ile2627Phe (I2627F) at the protein level, and results in the change of an Isoleucine to a Phenylalanine (ATC>TTC). Using alternate nomenclature, this variant has been previously published as BRCA2 8107A>T. BRCA2 Ile2627Phe has been observed in multiple breast/ovarian cancer families (Spitzer 2000, Balabas 2010, Stegel 2011, Lee 2014, Meisel 2017), and was strongly predicted by Lindor et al. (2012) to be pathogenic based on tumor pathology, clinical histories, family studies, and co-occurrence with deleterious variants. Functional studies demonstrated that BRCA2 Ile2627Phe displayed both reduced homology directed repair activity and an increase in centriole amplification when compared to wild-type, suggesting a disruption of BRCA2 function (Farrugia 2008, Guidugli 2013). BRCA2 Ile2627Phe was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ile2627Phe occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located within the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, we consider BRCA2 Ile2627Phe to be pathogenic.
# | Sample | Method | Observation |
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Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
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1 | germline | yes | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |