Exonic variants can lead to loss/gain of SREs
Variants annotated as synonymous, missense, nonsense, or frameshift
variants that disrupt exonic SREs have been identified in hereditary
cancer genes. Most of the published splicing assays on exonic SREs have
focused on variants in BRCA1, BRCA2 and the mismatch repair genes
(MLH1 , MSH2 , MSH6 and PMS2 ). We have
generated a comprehensive list of 81 variants in exonic SREs in these
genes that resulted in exon skipping in Supplementary Table 1
(BRCA1 , BRCA2 ) and Supplementary Table 2 (MLH1 ,MSH2 , MSH6 , PMS2 ). Exonic splicing variants in
other hereditary cancer genes include: a synonymous variant in theAPC gene, NM_000038.6:c.1869G>T [p.(Arg623=)],
detected in a familial adenomatous polyposis family, that leads to exon
14 skipping (Montera et al., 2001); and two nonsense NF1 variants
identified in Neurofibromatosis type 1 patients,
NM_000267.3:c.6792C>A and
NM_000267.3:c.6792C>G [both initially annotated as
p.(Tyr2264*)] that induce skipping of exon 37 and exons 36-37 (Baralle
et al., 2006; Messiaen, Callens, De Paepe, Craen, & Mortier, 1997). In
addition to single nucleotide substitutions, other types of exonic
variants can also disrupt SREs, such as small deletions, e.g.
NM_000059.3(BRCA2 ):c.470_474del (Sanz et al., 2010), and
duplications, e.g. NM_000535.6(PMS2 ):c.325dup (van der Klift et
al., 2015). Some variants can act through a combination of mechanisms.
For example, NM_000249.3(MLH1 ):c.840T>A
[p.(Tyr280*)] and NM_000249.3(MLH1 ):c.842C>T
[p.(Ala281Val)] have each been shown to disrupt an SRE and at the
same time create a new donor site leading to exon skipping and partial
exon deletion (Soukarieh et al., 2016).