Variant: NM_000059.4(BRCA2):c.8354C>T (p.Pro2785Leu)

CA025597

185253 (ClinVar)

Gene: BRCA2

Condition: BRCA2-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

UUID: 26c96c05-6746-44b4-ab80-27ddf5b83651

Approved on: 2025-12-03

Published on: 2025-12-02

HGVS expressions

NM_000059.4:c.8354C>T
NM_000059.4(BRCA2):c.8354C>T (p.Pro2785Leu)
NC_000013.11:g.32370424C>T
CM000675.2:g.32370424C>T
NC_000013.10:g.32944561C>T
CM000675.1:g.32944561C>T
NC_000013.9:g.31842561C>T
NG_012772.3:g.59945C>T
ENST00000470094.2:c.8354C>T
ENST00000528762.2:c.8354C>T
ENST00000530893.7:c.7985C>T
ENST00000665585.2:c.8354C>T
ENST00000666593.2:c.8354C>T
ENST00000700202.2:c.8354C>T
ENST00000700202.1:c.821C>T
ENST00000380152.8:c.8354C>T
ENST00000544455.6:c.8354C>T
ENST00000614259.2:c.8362C>T
ENST00000665585.1:c.919C>T
ENST00000680887.1:c.8354C>T
ENST00000380152.7:c.8354C>T
ENST00000544455.5:c.8354C>T
NM_000059.3:c.8354C>T

Likely Benign

• Met criteria codes: BS3 BP4

• Not Met criteria codes: BA1 BS1 BP5 PP4 PM2

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.8354C>T variant in BRCA2 is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 2785 (p.(Pro2785Leu)). 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). Reported by three calibrated studies to exhibit protein function similar to benign control variants (PMIDs:38417439, 39779857, 39779848) (BS3 met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of -0.008, which is below the recommended threshold of 0.18 for predicting no impact on BRCA2 via protein change. A SpliceAI score of 0.04 predicts no impact on splicing (score threshold <0.10) (BP4 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.15 (based on Family History LR=1.15), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMID: 31853058). In summary, this variant meets the criteria to be classified as a Likely benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS3, BP4).

Met criteria codes

• BS3: Reported by three calibrated studies to exhibit protein function similar to benign control variants (PMIDs:38417439, 39779857, 39779848) (BS3 met).
• BP4: This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of -0.008, which is below the recommended threshold of 0.18 for predicting no impact on BRCA2 via protein change. A SpliceAI score of 0.04 predicts no impact on splicing (score threshold <0.10) (BP4 met).

Not Met criteria codes

• BA1: 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).
• BS1: 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).
• BP5: Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.15 (based on Family History LR=1.15), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMID: 31853058).
• PP4: Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.15 (based on Family History LR=1.15), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMID: 31853058).
• 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).