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Table 1 Bioinformatics analysis and RNA results of variants with impact on splicing of BRCA2 exons 19, 20, 23 and 24.

From: Comprehensive splicing functional analysis of DNA variants of the BRCA2 gene by hybrid minigenes

Mutation

(HGVS)a

Bioinformatics analysisc

Splicing outcomed

RNA effect

(HGVS)a

Predicted protein effect

(HGVS)a

Exons 19-20b

 

WT Minigene 19-20: N_Sp(99%)

  

c.8378G > A (ex19)

[-] ESE, [+] hnRNP-B

N_Sp/Ex19 skipping

r.[8378g > a, 8332_8487del]

p.[G2793E, Ile2778_Gln2829del]

c.8486A > T (ex19)

↓score donor site/[-] SF2/ASF

Ex19 skipping

r.8332_8487del

p.Ile2778_Gln2829del

c.8487G > A (ex19)

↓score donor site/[-] SF2/ASF

Ex19 skipping

r.8332_8487del

p.Ile2778_Gln2829del

c.8487+1G > A (ivs19)

[-] Donor site disruption.

Ex19 skipping

r.8332_8487del

p.Ile2778_Gln2829del

c.8487+3A > G (ivs19)

↓score donor site.

Ex19 skipping

r.8332_8487del

p.Ile2778_Gln2829del

c.8488-2A > G (ivs19)

[-] Acceptor site

Intron retention/Ex20_12nt deletion/Ex20 skipping

r.[8487_8488ins8487+1_8488-1, 8488_8499del, r.8488_8632del]

p.[Gln2829fsX2, Trp2830_Lys2833del

Trp2830LysfsX13]

c.8488-1G > A (ivs19)

[-] Acceptor site

Intron retention/Ex20_12nt deletion/Ex20 skipping

r.[8487_8488ins8487+1_8488-1, 8488_8499del, r.8488_8632del]

p.[Gln2829fsX2, Trp2830_Lys2833del

Trp2830LysfsX13]

Exons 23-24 b

 

WT Minigene 23-24: N_Sp (100%)

  

c.8954-3C > G (ivs22)

[+] Acceptor site 2-nt upstream

Ex23_2-nt insertion

r.8954-2_8954-1ins

p.Val2985GlufsX4

c.8954-1_8955delinsAA (ivs22-ex23)

Disruption acceptor site

Ex23_51-nt deletion/Ex23 skipping/Ex23+24 skipping

r.[8954_9004del, 8954_9117del, 8954_9256del]

p.[Val2985_Thr3001del, Val2985GlyfsX3, p.Val2985_Thr3085del]

c.8969G > A (ex23)

[+] hnRNPA1; [+] hnRNP-B

N_Sp/Ex23_51-nt del

r.[8969g > a, 8954_9004del]

p.[W2990X, Val2985_Thr3001del]

c.9006A > T (ex23)

[-] SRp40; ↑score cryptic site

N_Sp/Ex23_51-nt del

r.[9006a > u, 8954_9004del]

p.[E3002D, Val2985_Thr3001del]

c.9076C > T (ex23)

[+] ESS

N_Sp/Ex23 skipping/Ex23+24 skipping

r.[9076c > u, 8954_9117del, 8954_9256del]

p.[Q3026X, Val2985GlyfsX3, Val2985_Thr3085del]

c.9117G > A (ex23)

[-] Donor site

Ex23 skipping/Ex23_51-nt del/Ex23+24 skipping

r.[8954_9117del, 8954_9004del, 8954_9256del]

p.[Val2985GlyfsX3, Val2985_Thr3001del, Val2985_Thr3085del]

c.9117+1G > T (ivs23)

[-] Donor site

Ex23 skipping

r.8954_9117del

p.Val2985GlyfsX3

c.9117+1G > A (ivs23)

[-] Donor site

Ex23 skipping

r.8954_9117del

p.Val2985GlyfsX3

c.9118-2A > G (ivs23)

[-] Acceptor site. Novel acceptor 7-nt downstream

Ex24_7-nt del/Ex24_24-nt del/Ex23+24 skipping

r.[9118_9124del, 9118_9141del, 8954_9256del]

p.[Val3040MetfsX20, Val3040_Gln3047del, Val2985_Thr3085del]

c.9248_9256+7del (ex24-ivs24)

[-] Donor site

Ex24 skipping/Ex24_43-nt del/Ex23+24 skipping

r.[9118_9256del, 9214_9256del, 8954_9256del]

p.[Val3040AspfsX18, Val3072AspfsX18, Val2985_Thr3085del

c.9256G > T (ex24)

[-] Donor site

Ex24 skipping/Ex23+24 skipping/Ex24_43-nt del/N_Sp

r.[9118_9256del, 8954_9256del, 9214_9256del,9256g > u]

p.[Val3040AspfsX18, Val2985_Thr3085del, Val3072AspfsX18, G3086X]

c.9256+1G > A (ivs24)

[-] Donor site

Ex24 skipping/Ex23+24 skipping/Ex24_43-nt del

r.[9118_9256del, 8954_9256del, 9214_9256del]

p.[Val3040AspfsX18, Val2985_Thr3085del, Val3072AspfsX18]

  1. aNomenclature of variants at DNA, RNA and protein levels follows the guidelines of the Human Genome Variation Society. bIntronic (ivs) or/and exonic (ex) location of each variant are indicated between brackets. cSummary of bioinformatics results with NNSPLICE and Human Splicing Finder. [-], disruption; [+], creation. ESE, Exonic Splicing Enhancer; ESS, Exonic Splicing Silencer; SF2/ASF and SRp40 are SR proteins that bind ESE/enhancer motifs; hnRNP proteins bind ESS/silencer motifs. dMajor isoforms are described. EX, exon; nt, nucleotide; del, deletion. Wild type minigene of exons 19 and 20 produced a minimal amount (1%) of exon 19 and exons 19+20 skipping. Variants with a relevant fraction of the wild type isoform are italicized (N_Sp: Normal Splicing). The relative proportions of each isoform are shown in Additional file 1, Figure S3.
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Breast Cancer Research

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