Variant: NM_000059.4(BRCA2):c.831T>G (p.Asn277Lys)

CA025568

38152 (ClinVar)

Gene: BRCA2

Condition: BRCA2-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

UUID: faec2530-d561-4e92-b253-ec7d7166e8a4

Approved on: 2024-06-12

Published on: 2024-06-12

HGVS expressions

NM_000059.4:c.831T>G
NM_000059.4(BRCA2):c.831T>G (p.Asn277Lys)
NC_000013.11:g.32332309T>G
CM000675.2:g.32332309T>G
NC_000013.10:g.32906446T>G
CM000675.1:g.32906446T>G
NC_000013.9:g.31804446T>G
NG_012772.3:g.21830T>G
ENST00000470094.2:c.831T>G
ENST00000528762.2:c.831T>G
ENST00000530893.7:c.462T>G
ENST00000665585.2:c.831T>G
ENST00000666593.2:c.831T>G
ENST00000700202.2:c.831T>G
ENST00000700201.1:c.*610T>G
ENST00000380152.8:c.831T>G
ENST00000544455.6:c.831T>G
ENST00000614259.2:c.831T>G
ENST00000680887.1:c.831T>G
ENST00000380152.7:c.831T>G
ENST00000530893.6:n.1029T>G
ENST00000544455.5:c.831T>G
ENST00000614259.1:n.831T>G
NM_000059.3:c.831T>G

Benign

• Met criteria codes: BP1_Strong BS3 BP5 BS1_Supporting

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.831T>G variant in BRCA2 is a missense variant predicted to cause substitution of Asparagine by Lysine at amino acid 277 (p.Asn277Lys). 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 0.00008331 in the European (non-Finnish) population, which is within the ENIGMA BRCA1/2 VCEP threshold (>0.00002 to ≤ 0.0001) for BS1_Supporting (BS1_Supporting met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0, score threshold <0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 33293522) (BS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.06 (based on Cosegregation LR=0.3; Pathology LR=1.27; Co-occurrence LR=1.88; Family History LR=0.0888), within the thresholds for Moderate benign evidence (LR ≥0.05 & <0.23) (BP5_Moderate met; PMID: 31131967). 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 (BS1_Supporting, BP1_Strong, BS3, BP5_Moderate).

Met criteria codes

• BP1_Strong: This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0, score threshold <0.1) (BP1_Strong met).
• BS3: Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 33293522) (BS3 met).
• BP5: Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.06 (based on Cosegregation LR=0.3; Pathology LR=1.27; Co-occurrence LR=1.88; Family History LR=0.0888), within the thresholds for Moderate benign evidence (LR ≥0.05 & <0.23) (BP5_Moderate met; PMID: 31131967).
• BS1_Supporting: 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 0.00008331 in the European (non-Finnish) population, which is within the ENIGMA BRCA1/2 VCEP threshold (>0.00002 to ≤ 0.0001) for BS1_Supporting (BS1_Supporting met).