Variant: NM_000059.4(BRCA2):c.8149G>T (p.Ala2717Ser)

CA025471

41564 (ClinVar)

Gene: BRCA2

Condition: BRCA2-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

UUID: 85356a31-9019-465e-a963-2b1162997a9e

Approved on: 2024-06-12

Published on: 2024-06-12

HGVS expressions

NM_000059.4:c.8149G>T
NM_000059.4(BRCA2):c.8149G>T (p.Ala2717Ser)
NC_000013.11:g.32363351G>T
CM000675.2:g.32363351G>T
NC_000013.10:g.32937488G>T
CM000675.1:g.32937488G>T
NC_000013.9:g.31835488G>T
NG_012772.3:g.52872G>T
ENST00000470094.2:c.8149G>T
ENST00000528762.2:c.8149G>T
ENST00000530893.7:c.7780G>T
ENST00000665585.2:c.8149G>T
ENST00000666593.2:c.8149G>T
ENST00000700202.2:c.8149G>T
ENST00000700202.1:c.616G>T
ENST00000380152.8:c.8149G>T
ENST00000544455.6:c.8149G>T
ENST00000614259.2:c.8157G>T
ENST00000665585.1:c.714G>T
ENST00000680887.1:c.8149G>T
ENST00000380152.7:c.8149G>T
ENST00000544455.5:c.8149G>T
NM_000059.3:c.8149G>T

Benign

• Met criteria codes: BP5_Strong BA1 BS3 BS2 BP4

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.8149G>T variant in BRCA2 is a missense variant predicted to cause substitution of Alanine by Serine at amino acid 2717 (p.Ala2717Ser). 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 0.001751 in the Latino/Admixed American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of -0.0816, which is below the recommended threshold of 0.18 for predicting no impact on BRCA2 via protein change. SpliceAI predictor score of 0.03 suggests that the variant has no impact on splicing (score threshold <0.10) (BP4 met). Reported by 3 calibrated studies to exhibit protein function similar to benign control variants (PMIDs: 29988080, 33609447, 32444794) (BS3 met). This variant has been observed in 2 individuals with features considered inconsistent with an FA-associated phenotype, and (Likely) Pathogenic variant seen in trans or variant is homozygous (total score 4 points) (BS2 met; Invitae internal contributor). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 2.288E-117 (based on Cosegregation LR=4.52E-08; Pathology LR=5.249E-08; Family History LR=1.995E-19; Case-Control LR=4.83E-84), below the threshold for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: Internal lab contributors). 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, BP4, BS3, BS2, BP5_Very strong).

Met criteria codes

• BP5_Strong: Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 2.288E-117 (based on Cosegregation LR=4.52E-08; Pathology LR=5.249E-08; Family History LR=1.995E-19; Case-Control LR=4.83E-84), below the threshold for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: 18375895).
• 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 0.001751 in the Latino/Admixed American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met).
• BS3: Reported by 3 calibrated studies to exhibit protein function similar to benign control variants (PMIDs: 29988080, 33609447, 32444794) (BS3 met).
• BS2: This variant has been observed in 2 individuals with features considered inconsistent with an FA-associated phenotype, and (Likely) Pathogenic variant seen in trans or variant is homozygous (total score 4 points) (BS2 met; Invitae internal contributor).
• BP4: This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of -0.0816, which is below the recommended threshold of 0.18 for predicting no impact on BRCA2 via protein change. SpliceAI predictor score of 0.03 suggests that the variant has no impact on splicing (score threshold <0.10) (BP4 met).