Variant: NM_000059.4(BRCA2):c.9925G>T (p.Glu3309Ter)

CA026335

52919 (ClinVar)

Gene: BRCA2

Condition: breast-ovarian cancer, familial, susceptibility to, 2

Inheritance Mode: Autosomal dominant inheritance

UUID: c0020d30-3b67-46e8-8a83-90ddcfd98a45

HGVS expressions

NM_000059.4:c.9925G>T
NM_000059.4(BRCA2):c.9925G>T (p.Glu3309Ter)
NC_000013.11:g.32398438G>T
CM000675.2:g.32398438G>T
NC_000013.10:g.32972575G>T
CM000675.1:g.32972575G>T
NC_000013.9:g.31870575G>T
NG_012772.3:g.87959G>T
ENST00000380152.8:c.9925G>T
ENST00000544455.6:c.9925G>T
ENST00000614259.2:c.9933G>T
ENST00000680887.1:c.9925G>T
ENST00000380152.7:c.9925G>T
ENST00000533776.1:n.513G>T
ENST00000544455.5:c.9925G>T
NM_000059.3:c.9925G>T

Uncertain Significance

• Met criteria codes: PM2_Supporting

• Not Met criteria codes: BS3 PS3 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 1.0.0

Evidence submitted by expert panel

ENIGMA BRCA1 and BRCA2 VCEP

The c.9925G>T variant in BRCA2 is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Glutamic acid at amino acid 3309 (p.Glu3309Ter). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). Nonsense variant predicted to cause a premature stop codon that is predicted to escape nonsense mediated decay, and lead to truncation of a region with unknown protein function (sequence up to BRCA2:p.Glu3309 is maintained) (PVS1 not met). Reported by two calibrated studies with discordant results. Exhibits protein function similar to benign control variants (PMID: 29988080) and pathogenic control variants (PMID: 18607349) (PS3 and BS3 not met). In summary, this variant meets the criteria to be 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 (PM2_Supporting).

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met).

Not Met criteria codes

• BS3: Reported by two calibrated studies with discordant results. Exhibits protein function similar to benign control variants (PMID: 29988080) and pathogenic control variants (PMID: 18607349) (PS3 and BS3 not met).
• PS3: Reported by two calibrated studies with discordant results. Exhibits protein function similar to benign control variants (PMID: 29988080) and pathogenic control variants (PMID: 18607349) (PS3 and BS3 not met).
• PVS1: Nonsense variant predicted to cause a premature stop codon that is predicted to escape nonsense mediated decay, and lead to truncation of a region with unknown protein function (sequence up to BRCA2:p.Glu3309 is maintained) (PVS1 not met).

Approved on: 2023-10-12

Published on: 2023-10-12