The BRCA2 c.8149G>T (p.Ala2717Ser) variant has been reported in ClinVar as Benign with expert panel review, and curated cancer resources did not identify it as a statistically significant hotspot while OncoKB describes it as likely neutral.1 This variant is present in population databases at a frequency above the BRCA2 ENIGMA BA1 threshold, with grpmax filtering allele frequency 0.00162114 in gnomAD v2.1 and 0.00163682 in gnomAD v4.1, supporting a benign population interpretation.2 In curated BRCA2 functional studies, this variant showed protein function similar to benign control variants, and associated RNA data showed no aberrant splicing, supporting BS3_Strong.3 Computational evidence does not support a damaging interpretation under the BRCA2 ENIGMA rules: the BayesDel no-AF score is -0.0816274, REVEL is 0.535, and no SpliceAI score demonstrating splice impact was identified, so PP3 is not met and BP4 could not be fully applied.4
Final classification
Benign
BA1BS3BP6
BRCA2
c.8149G>T
p.Ala2717Ser
This variant
The BRCA2 c.8149G>T (p.Ala2717Ser) variant has been reported in ClinVar as Benign with expert panel review, and curated cancer resources did not identify it as a statistically significant hotspot while OncoKB describes it as likely neutral.
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework (official ClinGen CSPEC/VCEP criteria-combination rules).
Classification rationale
BA1BS3BP6
Benign
BRCA2 c.8149G>T
BA1 + BS3 + BP6
→
Benign
3
vcep_specifications_table9_v1_2_2024_11_18cspec ↗
4
bayesdelrevelspliceai ↗cspec ↗
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_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 3 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 · 3
Strength
Supporting
Moderate
Strong
Very strong
BA1
stand-alone
Benign
This variant exceeds the BRCA2 ENIGMA BA1 population threshold. The grpmax filtering allele frequency is 0.00162114 in gnomAD v2.1 and 0.00163682 in gnomAD v4.1, both above the BA1 threshold of 0.001 in non-founder populations.
gnomAD v2.1 grpmax FAF 0.00162114gnomAD v4.1 grpmax FAF 0.00163682ENIGMA BA1 threshold FAF >0.001
BS3
strong
Benign
In the BRCA2 ENIGMA curated functional dataset, this variant was assigned BS3 Strong. Published calibrated functional studies showed protein function similar to benign control variants, and RNA data in the same curation entry showed no aberrant splicing.
ENIGMA Table 9 exact variant row: BS3 Strong for c.8149G>T p.(Ala2717Ser)
Assessed · not applied
· 7 not met · 8 not assessed
Pathogenic
PS1
No evidence was identified that this variant produces the same amino-acid change or the same predicted splice effect as a previously classified pathogenic or likely pathogenic BRCA2 variant.
PS3
Published functional data curated by the BRCA2 ENIGMA expert framework showed protein function similar to benign control variants rather than a damaging effect, so PS3 is not met.
PS4
No case-control evidence was identified showing that this variant is significantly enriched in affected individuals, and the variant is also observed at a population frequency that is too high to support PS4.
PM2
This variant is not absent from population databases.
PM3
No evidence was identified showing this variant in trans with another BRCA2 variant in a patient with a phenotype consistent with BRCA2-related Fanconi anemia.
PP1
No quantitative co-segregation evidence was identified for this variant in affected relatives.
PP3
This missense variant lies in the BRCA2 DNA-binding region, but the available computational evidence does not meet the ENIGMA PP3 threshold.
PP4
No variant-specific clinical-history likelihood ratio meeting ENIGMA thresholds was identified for this variant, so PP4 was not assessed.
Benign
BS1
Population frequency evidence was captured under BA1.
BS2
No evidence was identified showing this variant in individuals without features of BRCA2-related Fanconi anemia under the ENIGMA point-based BS2 framework.
BS4
No quantitative lack-of-segregation evidence was identified for this variant in affected relatives.
BP1
This missense variant is located at codon 2717 within the BRCA2 DNA-binding region defined by ENIGMA as a clinically important functional domain (amino acids 2481-3186).
BP4
The BayesDel no-AF score is -0.0816274, which is consistent with the benign side of the BRCA2 ENIGMA threshold, but BP4 for a missense variant in a clinically important domain also requires SpliceAI less than or equal to 0.1.
BP5
No variant-specific clinical-history likelihood ratio in the benign direction was identified for this variant, so BP5 was not assessed.
BP7
RNA evidence curated for this variant reported no aberrant splicing, but the available materials did not provide a direct ENIGMA BP7 assignment for this missense variant.
N/A · 10
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.00139272; MAF= 0.13927%, 2248/1614110 alleles, homozygotes = 2) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00169915; MAF= 0.16992%, 2005/1180000 alleles, homozygotes = 2); grpmax FAF= 0.00163682.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.00111433; MAF= 0.11143%, 315/282680 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.00207814; MAF= 0.20781%, 15/7218 alleles, homozygotes = 0); grpmax FAF= 0.00162114.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.14%
· 2248 / 1,614,110
2 hom · FAF 0.16%
2 hom · FAF 0.16%
European (non-Finnish) 2005 / 1,180,000 |
0.17% 2 hom |
Admixed American 77 / 60,014 |
0.13% |
Remaining individuals 67 / 62,508 |
0.11% |
European (Finnish) 65 / 64,022 |
0.1% |
African/African American 33 / 75,026 |
0.044% |
Ashkenazi Jewish 1 / 29,604 |
0.0034% |
+ 4 not observed (Amish, East Asian, Middle Eastern, South Asian)
gnomAD v2.1
0.11%
· 315 / 282,680
0 hom · FAF 0.16%
0 hom · FAF 0.16%
Remaining individuals 15 / 7,218 |
0.21% |
European (non-Finnish) 235 / 128,996 |
0.18% |
European (Finnish) 25 / 25,124 |
0.1% |
Admixed American 32 / 35,440 |
0.09% |
African/African American 7 / 24,970 |
0.028% |
Ashkenazi Jewish 1 / 10,364 |
0.0096% |
+ 2 not observed (East Asian, South Asian)
ClinVar
This variant has been reported in ClinVar as Benign (22 clinical laboratories) and as Likely benign (11 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Benign by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 41564)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.535. BayesDel score = -0.0816274.
Functional
Likely Neutral
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV66460731, n = 3 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 8 PMIDs not cited in assessment
18375895 ↗
Clinical classification of BRCA1 and BRCA2 DNA sequence variants: the value of cytokeratin profiles and evolutionary analysis--a report from the kConFab Investigators.
ONCOKB
29394989 ↗
Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches.
ONCOKB
11802209 ↗
Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population.
CLINVAR
12955716 ↗
Analysis of BRCA1 and BRCA2 genes in Spanish breast/ovarian cancer patients: a high proportion of mutations unique to Spain and evidence of founder effects.
CLINVAR
19471317 ↗
Impact of BRCA1 and BRCA2 variants on splicing: clues from an allelic imbalance study.
CLINVAR
20104584 ↗
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR