ClinVar

Description

The p.Arg2336Pro variant has been previously reported in the literature in at least one individual with hereditary breast cancer (Laitman 2011). In addition, this variant has been previously reported in the UMD database (2x as causal), and the BIC database (5x as clinically relevant). The variant is also reported in dbSNP (rs28897743) and may be a low frequency pathogenic variant in one or more populations. The p.Arg2336Pro variant occurs in the last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, in one study, RNA was extracted from lymphoblastoid cell lines and an increase of alternative splicing was observed ('Exons 12 and 13 skipped'), increasing the likelihood this variant has clinical significance (Houdayer 2012). Another variant at the same position (c.7007G>A; p.Arg2336His) has been shown to induce aberrant splicing (Thomassen 2006), also increasing the likelihood a variant at this position is clinically significant. Furthermore, in-silico analysis (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing in 3 of 5 different programs. In summary, based on the above information, this variant is classified as Pathogenic.