Table 1. Classification of putative BRCA1 splicing mutations.
| BIC nomenclature | HGVS nomenclature | in vitro splicing result | in vitro splicing result (HGVS) | protein change (HGVS) | Family ID | Proband(s) analysed (phenoptype,onset) | Family history | Ethnicity |
| A: Severe impact on splicing * | ||||||||
| BRCA1 variants within invariant splice sites | ||||||||
| IVS2−1G>C | c.81−1G>C | Δ7nt 5′ of exon 3 | r.81_87del | p.Leu30* | 09_2506 | #001 (n.a.) | BC (40 y), 4× OC (40 y, 52 y, 65 y, 68 y) | European |
| IVS4−1G>C | c.135−1G>C | enhanced Δ exon 5 | enhanced r.135__212del | p.[Phe45_Lys71del] | 09_3489 | #001 (n.a.) | 4× BC (30 y, 33 y, 41 y, 47 y), 2× OC (50 y, 70 y*) | Afghan |
| IVS5+1G>C | c.212+1G>C | enhanced Δ22nt 3′ of exon 5 | enhanced r.191_212del | p.Cys64* | 09_1855 | #001 (BC, 38 y) | 1× BCbil (33 y+33 y), 3× BC (35 y, 38 y*, 42 y), 1× OC (55 y*) | European |
| IVS17−2A>G | c.5075−2A>G | Δ exon 18 | r.5075_5152del | p.Asp1692_Trp1718delinsGly | 03_0847 | #001 (BC+OC, 42 y+47 y) | 1× BC+OC (42 y+47 y*) | European |
| IVS18+1G>C | c.5152+1G>C | Δ exon 18 | r.5075_5152del | p.Asp1692_Trp1718delinsGly | 09_0879 | #002 (BC, 35 y) | 3× BC (35 y*, 71 y, 73 y) | European |
| IVS18+1G>C | c.5152+1G>C | Δ exon 18 | r.5075_5152del | p.Asp1692_Trp1718delinsGly | 09_0756 | #002 (BC, 72 y, male) | 3× BC (37 y, 50 y, 72 y*) | European |
| IVS18−2delA | c.5153−2delA | Δ exon 19 | r.5153_5193del | p.Trp1718Serfs*1 | 09_0329 | #001 (n.a., MTX) | 6× BC (27 y*, 31 y*, 35 y*, 48 y, 50 y, 60 y) | European |
| IVS18−2delA | c.5153−2delA | Δ exon 19 | r.5153_5193del | p.Trp1718Serfs*1 | 09_1131 | #001 (n.a.) | 1× BCbil (43 y+55 y*) together with OC (67 y*) | European |
| IVS19+1delG | c.5193+1delG | Δ last nt of exon 19 | r.5193del | p.Glu1731Aspfs*33 | 09_2891 | #001 (BC, 32 y) | 1× BC (32 y*), 1OC (70 y*) | European |
| IVS19+2T>G | c.5193+2T>G | Δ exon 19 | r.5153_5193del | p.Trp1718Serfs*1 | 09_2062 | #001 (BC, 29 y) | 2× BC (29 y*, 43 y) | European |
| IVS19−1G>T | c.5194−1G>T | Δ exon 20, Δ13nt 5′ of exon 20 | r.[5194_5277del, 5194_5206del] | p.[His1732_Lys1759del, His1732Serfs*28] | 09_1932 | #001 (BCbil, 37 y+40 y) | 1× BCbil (37 y+40 y*), 2× BC (43 y, 71 y) | European |
| IVS20−1G>A | c.5278−1G>A | enhanced Δ exon 21, Δ8nt 5′ of exon 21 | enhanced r.5278_5332del, r.5278_5286del | p.[Phe1761Asnfs*13, Phe1761Glyfs*66] | 09_3614 | #001 (BC, 41 y) | 2× BC (41 y*, 42 y) | European |
| IVS21−1G>T | c.5333−1G>T | Δ exon 22 | r.5333_5406del | p.Asp1778Glyfs*26 | 09_1499 | #001 (n.a.), #002 (BC, 37 y), #003 (BCbil, 39 y+56 y) | 2× BCbil (39 y+56 y*, 56 y+56 y), 2× BC (37 y*, 65 y) | European |
| IVS22+2delT | c.5406+2delT | Δ exon 22 | r.5333_5406del | p.Asp1778Glyfs*26 | 09_1288 | #001 (BCbil, 38 y+39 y), #002 (BCbil, 29 y+43 y), #006 (BronC, 85 y) | 2× BCbil (38 y+39 y*, 29 y+43 y*) | European |
| Intronic BRCA1 variants outside invariant splice sites | ||||||||
| IVS11+3A>G | c.4096+3 A>G | enhanced Δ exon 11, Δ3309nt 3′ of exon 11 | enhanced r.[671_4096del, 787_4096del] | p.[Ala224_Leu1365del, Ser264_Leu1365del] | 12_0909 | #001 (BC, 62 y) | 3× BC (62 y*, 81 y, 51 y), 1× OC (55 y) | European |
| IVS16+3G>C | c.4986+3 G>C | Ins 65 nt intron 16 | r.4986+1_4986+65ins | p.Met1663Valfs*14 | 09_0351 | #001 (BC, 33 y) | 2× BC (32 y, 33 y*), 1× BC+OC (39 y, 64 y), 1OC (70 y) | European |
| IVS16+4A>G | c.4986+4 A>G | Ins 65 nt intron 16 | r.4986+1_4986+65ins | p.Met1663Valfs*14 | 12_0899 | #001 (BCbil, 34 y+50 y), #009 (BC, 31 y) | 1× BCbil (34 y+50 y*), 2× BC (31 y*, 40 y) | European |
| IVS16+5G>A | c.4986+5 G>A | Ins 65 nt intron 16 | r.4986+1_4986+65ins | p.Met1663Valfs*14 | 09_4089 | #001 (BC, 36 y) | 4× BC (20 y, 36 y*, 50 y, 50 y) | Arabian |
| IVS22+3A>T | c.5406+3 A>T | Δ exon 22 | r.5333_5406del | p.Asp1778Glyfs*26 | TU367 | #20226 (BC, 40 y) | 2× BC (40 y*, 52 y) | European |
| IVS22+4A>G | c.5406+4 A>G | Δ exon 22 | r.5333_5406del | p.Asp1778Glyfs*26 | GH188 | #11896 (OvCa, 60J) | 1× OV (60 y*), DCIS (64 y), OvX (38 y*) | European |
| Exonic BRCA1 variants | ||||||||
| 4304G>A,Q1395Q | c.4185G>A, p.Gln1395Gln | Δ exon 12 | r.4097_4185del | p.Gly1366Alafs*7 | TU235 | #19896 (OC, 61 y) | 4× BC (34 y*, 43 y, 68 y, 57 y), 2× OC (60 y, 61 y*) | European |
| 4794G>A,E1559K | c.4675G>A, p.Glu1559Lys | Δ11nt 3′of exon 15 | r.4665_4675del | p.Gln1556Glyfs*13 | 09_3575 | #003 (OC, 50 y) | 1× BC (44), 2× OC (47 y, 50 y*) | European |
| 5193G>C,D1692H | c. 5074G>C, p.Asp1629His | Ins 153 nt intron 17, enhanced Δ exon 17 | r.5074+1_5074+153ins, enhanced 4987_5074del] | p.[Asp1692Glyfs *14, Val1665Serfs*7] | 09_3943 | #001 (BC, 27 y) | 1× BC (27 y*) | European |
| 5527G>C,G1803A | c.5408G>C, p.Gly1803Ala | Δ exon 23 | r.5407_5467del | p.Gly1803Glnfs*10 | 09_ 2219 | #001 (OC, 45 y) | 1× BC (41 y), 4× OC (45 y*, 45 y, 45 y*, 53 y) | European |
| B: Partial impact on splicing * | ||||||||
| IVS4−18T>G | c.135−18T>G | enhanced Δ exon 5 | enhanced r.135__212del | p.[Phe45_Lys71del] | 09_1411 | #001 (BC, 45 y) | 3× BC (45 y*, 45 y, 83 y) | European |
| 710C>T,C197C | c.591C>T, p.Cys197Cys | enhanced Δ exon 9 and 9/10 | enhanced r.548_593del, r.548_670del | p.[Gly183Cysfs*16, Gly183_Lys223del] | 09_1472 | #001 (n.a.) | 2× BC (36 y, 52 y) | European |
| 710C>T,C197C | c.591C>T, p.Cys197Cys | enhanced Δ exon 9 and 9/10 | enhanced r.548_593del, r.548_670del | p.[Gly183Cysfs*16, Gly183_Lys223del] | 09_2106 | #001 (BCbil, 50 y+55 y) | 2× BCbil (50 y+55 y*, 59 y+65 y), 4× BC (36 y, 65 y, 70 y, 70 y) | European |
| 787A>G,K223R | c.668A>G, p.Lys223Arg | enhanced Δ exon 10 | enhanced r.594_670del | p.Val199Cysfs*2, p.Lys223Arg | 12_0621 | #001 (BC, 32 y), #002 (BC, 58 y) | 4× BC (32 y*, 52 y, 58 y*, 40 y); | European |
| C: No effect on splicing observed * | ||||||||
| IVS5+23T>A | c.212+23 T>A | / | / | / | 09_3716 | #001 (BC, 40 y) | 2× BC (40 y*, 50 y) | European |
| IVS9−34T>C | c.594−34T>C | / | / | / | 09_2602 | #001 (BC, 21 y) | 2× BC (21 y*, 44 y) | Turkish |
| IVS18−6C>A | c.5152−6C>A | / | / | / | 09_1469 | #001 (DCIS, 53 y) | 2× BC (53 y*, 75 y), 1× DCIS (53 y*) | European |
| IVS20+15C>T | c.5277+15C>T | / | / | / | 09_2627 | #001 (BC, 35 y) | 1× BC (35 y*) | European |
| IVS21+13G>T | c.5332G>T | / | / | / | 09_2376 | #001 (BC, 42 y) | 2× BC (42 y*, 45 y) | European |
A: Variants that severely affect splicing, B: Variants having a partial effect only, and C: Variants that do not affect processing of BRCA1 pre-mRNA species in PBL.
*
Variants with severe impact on splicing are considered as likely pathogenic (class 4) according to the classification system proposed by Plon et al., [42], while variants with only partial effects on splicing remain of uncertain clinical significance (class 3). Variant descriptions (BIC nomenclature, HGVS nomenclature), consequences on transcript- and protein levels, family IDs, analyzed index patients (phenotypes, age at onset), family histories (phenotypes, age at onset) and ethnic backgrounds are given. Family members carrying the same BRCA1 variant are indicated (asterisk). All other listed family members were not available for analysis. Abbreviation: BC = breast cancer; OC = ovarian cancer; n.a. = not affected; bil = bilateral; ProC = prostate carcinoma; MTX = mastectomy; DCIS = Ductal carcinoma in situ.