Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000059.4(BRCA2):c.8059G>T (p.Val2687Phe)

CA025429

52491 (ClinVar)

Gene: BRCA2 (HGNC:675)
Condition: BRCA2-related cancer predisposition (MONDO:0700269)
Inheritance Mode: Autosomal dominant inheritance
UUID: aa16180c-69d0-4d51-9b11-ecfb4e829052
Approved on: 2025-08-18
Published on: 2025-08-18

HGVS expressions

NM_000059.4:c.8059G>T
NM_000059.4(BRCA2):c.8059G>T (p.Val2687Phe)
NC_000013.11:g.32363261G>T
CM000675.2:g.32363261G>T
NC_000013.10:g.32937398G>T
CM000675.1:g.32937398G>T
NC_000013.9:g.31835398G>T
NG_012772.3:g.52782G>T
ENST00000470094.2:c.8059G>T
ENST00000528762.2:c.8059G>T
ENST00000530893.7:c.7690G>T
ENST00000665585.2:c.8059G>T
ENST00000666593.2:c.8059G>T
ENST00000700202.2:c.8059G>T
ENST00000700202.1:c.526G>T
ENST00000380152.8:c.8059G>T
ENST00000544455.6:c.8059G>T
ENST00000614259.2:c.8067G>T
ENST00000665585.1:c.624G>T
ENST00000680887.1:c.8059G>T
ENST00000380152.7:c.8059G>T
ENST00000544455.5:c.8059G>T
NM_000059.3:c.8059G>T
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Uncertain Significance

Met criteria codes 2
PS3 PP3
Not Met criteria codes 6
PM2 BS1 BP7 BP5 BA1 PP4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA2 Version 1.2.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
ENIGMA BRCA1 and BRCA2 VCEP
The c.8059G>T variant in BRCA2 is a missense variant predicted to cause substitution of Valine by Phenylalanine at amino acid 2687 (p.(Val2687Phe)). 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). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.37, above the recommended threshold of 0.30 for prediction of impact on BRCA2 function via protein change. A SpliceAI score of 0 predicts no impact on splicing (score threshold <0.10) (PP3 met). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:38417439, 39779857, 39779848) (PS3 met). mRNA experimental analysis indicates no impact on splicing (Internal lab contributor) but is not applied as strong evidence against pathogenicity since missense impact has not been excluded (BP7_Strong (RNA) not met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.42 (based on Family History LR=1.42), 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 Variant of uncertain significance for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PS3, PP3).
Met criteria codes
PS3
Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:38417439, 39779857, 39779848) (PS3 met).
PP3
This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.37, above the recommended threshold of 0.30 for prediction of impact on BRCA2 function via protein change. A SpliceAI score of 0 predicts no impact on splicing (score threshold <0.10) (PP3 met).
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).
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).
BP7
This is a missense variant inside a key functional domain. Impact via the protein change has been shown to exhibit function similar to pathogenic control variants (PMID: 35736817). mRNA experimental analysis indicates no impact on splicing (Internal lab contributor) but is not applied as strong evidence against pathogenicity since missense impact has not been excluded (BP7_Strong (RNA) not met).
BP5
Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.42 (based on Family History LR=1.42), 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).
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).
PP4
Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.42 (based on Family History LR=1.42), 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).
Curation History
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