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]
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  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
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Variant: NM_000059.4(BRCA2):c.9976A>T (p.Lys3326Ter)

CA026350

38266 (ClinVar)

Gene: BRCA2
Condition: breast-ovarian cancer, familial, susceptibility to, 2
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: d7eeea50-bae6-4d66-8a75-a47e13cc51e6

HGVS expressions

NM_000059.4:c.9976A>T
NM_000059.4(BRCA2):c.9976A>T (p.Lys3326Ter)
NC_000013.11:g.32398489A>T
CM000675.2:g.32398489A>T
NC_000013.10:g.32972626A>T
CM000675.1:g.32972626A>T
NC_000013.9:g.31870626A>T
NG_012772.3:g.88010A>T
ENST00000470094.2:c.*499A>T
ENST00000528762.2:c.*1343A>T
ENST00000530893.7:c.9607A>T
ENST00000665585.2:c.*1538A>T
ENST00000700202.2:c.9925A>T
ENST00000700202.1:c.2392A>T
ENST00000700203.1:n.2103A>T
ENST00000380152.8:c.9976A>T
ENST00000544455.6:c.9976A>T
ENST00000614259.2:c.9984A>T
ENST00000680887.1:c.9976A>T
ENST00000380152.7:c.9976A>T
ENST00000544455.5:c.9976A>T
NM_000059.3:c.9976A>T

Benign

Met criteria codes 3
BS3 BA1 BP5_Strong
Not Met criteria codes 3
BS2 PS4 PVS1

Evidence Links 1

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 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
ENIGMA BRCA1 and BRCA2 VCEP
The c.9976A>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 Lysine at amino acid 3326 (p.Lys3326Ter). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.00813 in the European (non-Finnish) population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 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 one calibrated study to exhibit protein function similar to benign control variants (PMID: 29988080) (BS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 3.09E-263 (based on Cosegregation LR=0.001; Pathology LR=1.864E-35; Co-occurrence LR=0.0001; Case-Control LR=1.66E-221), below the threshold for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: 18451181, Internal lab contributor). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BA1, BS3, BP5_Very strong).
Met criteria codes
BS3
Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 29988080) (BS3 met). Reported by Mesman et al., 2019 (PMID: 29988080) to have no impact on function.
Reported by one calibrated study to affect protein function similar to benign control variants (PMID:29988080) (BS3 met). PubMed:29988080
BA1
The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.00813 in the European (non-Finnish) population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met).
BP5_Strong
Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 3.09E-263 (based on Cosegregation LR=0.001; Pathology LR=1.864E-35; Co-occurrence LR=0.0001; Case-Control LR=1.66E-221), below the threshold for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: 18451181).
Not Met criteria codes
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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: 2024-04-24
Published on: 2024-04-24
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