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
BRCA2
Final classification
Benign
BRCA2 c.8149G>T · p.Ala2717Ser
BRCA2
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 ↗
Gene diagram
· NM_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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