The BRCA2 NM_000059.4:c.2820A>G (p.(Gln940=), p.(Q940=)) variant has been reported in ClinVar as likely benign, including review by the ENIGMA expert panel and multiple clinical laboratories.1 This variant is present at very low frequency in population databases, with 1/250640 alleles in gnomAD v2.1 (AF 0.00040%) and 1/1613806 alleles in gnomAD v4.1 (AF 0.00006%), which does not meet ENIGMA benign stand-alone or strong population thresholds and does not satisfy PM2 absence criteria.2 In silico splicing analysis predicts no significant splice impact, with a SpliceAI maximum delta score of 0.00, and the synonymous p.(Gln940=) change lies outside the BRCA2 clinically important domains defined by ENIGMA, supporting BP1_Strong and arguing against PP3.3
Final classification
Likely benign
BP1BP6
BRCA2
c.2820A>G
p.Gln940=
This variant
The BRCA2 NM_000059.4:c.2820A>G (p.(Gln940=), p.(Q940=)) variant has been reported in ClinVar as likely benign, including review by the ENIGMA expert panel and multiple clinical laboratories.
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework (official CSPEC/VCEP criteria-combination rules).
Classification rationale
BP1BP6
Likely benign
BRCA2 c.2820A>G
BP1 + BP6
→
Likely benign
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 15 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
BP1
strong
Benign
This is a synonymous BRCA2 variant, p.(Gln940=), located outside the clinically important BRCA2 domains defined by ENIGMA (PALB2-binding aa 10-40 and DNA-binding aa 2481-3186), and SpliceAI predicts no splice effect with a maximum delta score of 0.00, which is below the <=0.10 threshold. This meets BP1_Strong.
Protein consequence p.(Gln940=).Codon 940 lies outside aa 10-40 and aa 2481-3186.SpliceAI max delta score 0.00.
Assessed · not applied
· 4 not met · 11 not assessed
Pathogenic
PS1
No evidence was identified that this variant has the same proven pathogenic protein or splicing consequence as a previously classified pathogenic BRCA2 variant, so PS1 was not assessed further.
PS3
No variant-specific damaging functional study meeting the ENIGMA BRCA2 PS3 framework was identified for this variant.
PS4
No case-control or multifactorial evidence was identified showing this variant is significantly enriched in affected individuals compared with controls.
PM2
This variant is not absent from population databases, so PM2 is not met.
PM3
No evidence was identified for occurrence with another BRCA2 variant in a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 was not assessed further.
PP1
No quantitative segregation data were identified for this variant, so PP1 was not assessed.
PP3
Available computational evidence does not support a splice-altering effect.
PP4
No variant-specific multifactorial clinical-history likelihood ratio supporting pathogenicity was identified for this variant, so PP4 was not assessed.
Benign
BA1
This variant does not meet the ENIGMA BA1 population threshold.
BS1
Available population data do not support BS1.
BS2
No evidence was identified showing occurrence in individuals without features of BRCA2-related Fanconi anemia sufficient for ENIGMA BS2 scoring.
BS3
No variant-specific benign functional study meeting the ENIGMA BRCA2 BS3 framework was identified for this variant.
BS4
No quantitative lack-of-segregation evidence was identified for this variant, so BS4 was not assessed.
BP5
No variant-specific multifactorial clinical-history likelihood ratio supporting a benign interpretation was identified for this variant, so BP5 was not assessed.
BP7
SpliceAI predicts no splice impact, but no qualifying RNA study showing a benign transcript outcome was identified for this variant, so BP7 was not assessed beyond computational evidence alone.
N/A · 11
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP4
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.19653e-07; MAF= 0.00006%, 1/1613806 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.23065e-05; MAF= 0.00223%, 1/44830 alleles, homozygotes = 0).
v2.1
This variant is present in gnomAD v2.1 (AF= 3.98979e-06; MAF= 0.00040%, 1/250640 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.43833e-05; MAF= 0.00544%, 1/18388 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,613,806
0 hom
0 hom
East Asian 1 / 44,830 |
0.0022% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
0.0004%
· 1 / 250,640
0 hom
0 hom
East Asian 1 / 18,388 |
0.0054% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Likely benign (6 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Likely benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Unknown Oncogenic Effect
OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links