Variant: NM_000059.4(BRCA2):c.425+1G>A

CA019789

142617 (ClinVar)

Gene: BRCA2

Condition: BRCA2-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

UUID: 6c23a8e0-eb1f-4105-a6df-12db7043631d

Approved on: 2025-05-23

Published on: 2025-05-23

HGVS expressions

NM_000059.4:c.425+1G>A
NM_000059.4(BRCA2):c.425+1G>A
NC_000013.11:g.32325185G>A
CM000675.2:g.32325185G>A
NC_000013.10:g.32899322G>A
CM000675.1:g.32899322G>A
NC_000013.9:g.31797322G>A
NG_012772.3:g.14706G>A
ENST00000470094.2:c.425+1G>A
ENST00000528762.2:c.425+1G>A
ENST00000530893.7:c.56+1G>A
ENST00000665585.2:c.425+1G>A
ENST00000666593.2:c.425+1G>A
ENST00000700202.2:c.425+1G>A
ENST00000700200.1:n.296+1G>A
ENST00000700201.1:c.*204+1G>A
ENST00000380152.8:c.425+1G>A
ENST00000544455.6:c.425+1G>A
ENST00000614259.2:c.425+1G>A
ENST00000680887.1:c.425+1G>A
ENST00000380152.7:c.425+1G>A
ENST00000530893.6:n.623+1G>A
ENST00000544455.5:c.425+1G>A
ENST00000614259.1:n.425+1G>A
NM_000059.3:c.425+1G>A

Uncertain Significance

• Not Met criteria codes: PM2 PVS1

Expert Panel

ENIGMA BRCA1 and BRCA2 VCEP

Criteria Specification Information

Criteria Specification: ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA2 Version 1.1.0

Evidence submitted by expert panel

ENIGMA BRCA1 and BRCA2 VCEP

The c.425+1G>A variant is an intronic variant within the native donor 1,2 splice site occurring in intron 4 of the BRCA2 gene. It is predicted to cause out-of-frame skipping of exon 4, resulting in a frameshift leading to nonsense mediated decay. All variants at this splice site score very similar with SpliceAI predicting exon 4 skipping, however several variants at this splice site exhibit complex patterns of splicing with only partial prediction of nonsense mediated decay. BRCA2 c.425+2T>C RNA data (RT-PCRseq) shows skipping of exon 4 at 32.55% PSI, with in-frame skipping of exons 4 and 5 at 7.17% PSI. BRCA2:c.425G>A RNA data (RT-PCRseq) shows exon 4 skipping at 36.73% PSI, in-frame skipping of exons 4 and 5 at 13.69% PSI, and out of frame skipping of exons 3 and 4 at 4.05% PSI. Similarly, BRCA2:c.425G>T RNA data (RT-PCRseq) shows exon 4 skipping at 26.85% PSI, skipping of exons 4-5 at 9.63% PSI, and exon 4-7 skipping at 3.84% PSI. Normally spliced transcripts contained nearly 100% WT allele (internal laboratory contributor). Published data also indicates these variants (c.425+2T>C, c.425G>A, c.425G>T) retain partial function and have clinical phenotypes consistent with benign variants (PMID: 33469799; 32398771). Based on this, we have not assigned pathogenic evidence at any strength (PVS1_N/A) to exon 4 donor site variants. This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting. In summary, this variant did not meet any criteria and is classified as a Variant of uncertain significance for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (v1.2).

Not Met criteria codes

• PM2: This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting.(PM2_Supporting, BS1, and BA1 are not met).
• PVS1: The c.425+1G>A variant is an intronic variant within the native donor 1,2 splice site occurring in intron 4 of the BRCA2 gene. It is predicted to cause out-of-frame skipping of exon 4, resulting in a frameshift leading to nonsense mediated decay. All variants at this splice site score very similar with SpliceAI predicting exon 4 skipping, however several variants at this splice site exhibit complex patterns of splicing with only partial prediction of nonsense mediated decay. BRCA2 c.425+2T>C RNA data (RT-PCRseq) shows skipping of exon 4 at 32.55% PSI, with in-frame skipping of exons 4 and 5 at 7.17% PSI. BRCA2:c.425G>A RNA data (RT-PCRseq) shows exon 4 skipping at 36.73% PSI, in-frame skipping of exons 4 and 5 at 13.69% PSI, and out of frame skipping of exons 3 and 4 at 4.05% PSI. Similarly, BRCA2:c.425G>T RNA data (RT-PCRseq) shows exon 4 skipping at 26.85% PSI, skipping of exons 4-5 at 9.63% PSI, and exon 4-7 skipping at 3.84% PSI. Normally spliced transcripts contained nearly 100% WT allele (internal laboratory contributor). Published data also indicates these variants (c.425+2T>C, c.425G>A, c.425G>T) retain partial function and have clinical phenotypes consistent with benign variants (PMID: 33469799; 32398771). Based on this, we have not assigned pathogenic evidence at any strength (PVS1_N/A) to exon 4 donor site variants.