The BRCA2 c.8149G>T (p.Ala2717Ser) variant has been observed in somatic cancers in COSMIC (COSV66460731, n=3) and has also been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 expert panel classifies it as benign.1 This variant is common in population databases, with gnomAD v2.1 group-maximum filter allele frequency 0.00162114 and gnomAD v4.1 group-maximum filter allele frequency 0.00163682, both above the ENIGMA BA1 threshold of 0.001.2 Calibrated BRCA2 functional evidence supports a benign effect: ENIGMA Table 9 assigns BS3 Strong based on three studies showing function similar to benign controls, with no aberrant RNA result listed.3 SpliceAI predicts no significant splice effect for this variant, with a maximum delta score of 0.03, which argues against splice disruption.4
BRCA2
Final classification
Benign
BRCA2 c.8149G>T · p.Ala2717Ser
BRCA2
The BRCA2 c.8149G>T (p.Ala2717Ser) variant has been observed in somatic cancers in COSMIC (COSV66460731, n=3) and has also been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 expert panel classifies it as benign.
ENIGMA BRCA1 and BRCA2 Specification v1.2 final-classification framework (Table 3 override from the official CSPEC/VCEP ruleset).
Classification rationale
BA1BS1BS3BP6
Benign
BRCA2 c.8149G>T
BA1 + BS1 + BS3 + BP6
→
Benign
3
vcep_specifications_table9_v1_2_2024_11_18cspec ↗
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 4 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).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
Functional
Likely Neutral
OncoKB classifies this variant as Likely Neutral; biological effect: 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