The BRCA2 c.9976A>T (p.Lys3326Ter, K3326*) variant has been observed in somatic cancers in COSMIC (18 occurrences) and has been reported in ClinVar with an expert-panel benign classification.1 This variant is common in population databases, including gnomAD v2.1 with an overall allele frequency of 0.64680% and grpmax FAF of 0.849119%, and gnomAD v4.1 with an overall allele frequency of 0.79156%; these values are above the BRCA2 ENIGMA BA1 (>0.1%) and BS1 (>0.01%) thresholds.2 Calibrated BRCA2 functional evidence supports a benign effect, with the expert specification assigning BS3 Strong to this exact variant based on protein function similar to benign controls.3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.07.4
Final classification
Benign
BA1BS1BS3BP6
BRCA2
c.9976A>T
p.Lys3326Ter
This variant
The BRCA2 c.9976A>T (p.Lys3326Ter, K3326*) variant has been observed in somatic cancers in COSMIC (18 occurrences) and has been reported in ClinVar with an expert-panel benign classification.
ClinGen ENIGMA BRCA1/BRCA2 Specification v1.2.0 Table 3 final-classification framework (CSPEC/VCEP primary authority)
Classification rationale
BA1BS1BS3BP6
Benign
BRCA2 c.9976A>T
BA1 + BS1 + BS3 + BP6
→
Benign
3
vcep_specifications_table9_v1_2_2024_11_18cspec ↗
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 · 4 applied · 10 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 · 4
Strength
Supporting
Moderate
Strong
Very strong
BA1
stand-alone
Benign
This variant is common in population databases. In gnomAD v2.1, grpmax FAF is 0.00849119 (0.849119%), which is above the BRCA2 ENIGMA BA1 threshold of 0.001 (0.1%); the overall allele frequency is 0.00646801 (0.64680%), and gnomAD v4.1 also shows an overall allele frequency of 0.00791559 (0.79156%).
gnomAD v2.1 grpmax FAF 0.00849119 > BA1 threshold 0.001gnomAD v2.1 total AF 0.006468011825/282158 alleles
BS1
strong
Benign
The population frequency is also above the BRCA2 ENIGMA BS1 threshold. In gnomAD v2.1, grpmax FAF is 0.00849119 (0.849119%), which is above the BS1 Strong threshold of 0.0001 (0.01%).
gnomAD v2.1 grpmax FAF 0.00849119 > BS1 Strong threshold 0.0001gnomAD v4.1 grpmax FAF 0.00883986
BS3
strong
Benign
Calibrated functional evidence in the BRCA2 expert specification supports a benign effect. This exact variant is listed as BS3 Strong, with protein function similar to benign control variants; SpliceAI also predicts no significant splice impact (max delta score 0.07).
ENIGMA Table 9 exact-variant entry assigns BS3 StrongTable 9 notes protein function similar to benign controlsSpliceAI max delta score 0.07
Assessed · not applied
· 3 not met · 7 not assessed
Pathogenic
PS2
No confirmed de novo data with parental relationships and phenotypic specificity were identified, so PS2 was not assessed.
PS3
Available functional evidence does not support a damaging effect.
PS4
Available evidence does not show the marked enrichment in affected individuals required for PS4.
PM2
This variant is not absent from population databases.
PM3
No evidence was identified for this variant in trans with another BRCA2 variant in a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 was not assessed.
PP1
No quantitative co-segregation data were identified for this variant, so PP1 was not assessed.
PP4
No qualifying multifactorial clinical likelihood ratio supporting pathogenicity was identified for this variant, so PP4 was not assessed.
Benign
BS2
No point-based evidence in unaffected individuals without features of BRCA2-related Fanconi anemia was identified, so BS2 was not assessed.
BS4
No quantitative lack-of-segregation likelihood ratio was identified for this variant, so BS4 was not assessed.
BP5
No qualifying multifactorial clinical likelihood ratio against pathogenicity was identified in the retrieved structured BRCA2 materials, so BP5 was not assessed.
N/A · 14
PVS1 · PS1 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · PP5 · BP1 · BP2 · BP3 · BP4 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.00791559; MAF= 0.79156%, 12777/1614156 alleles, homozygotes = 72) and has highest observed frequency in the Amish population (AF= 0.0351648; MAF= 3.51648%, 32/910 alleles, homozygotes = 2); grpmax FAF= 0.00883986.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.00646801; MAF= 0.64680%, 1825/282158 alleles, homozygotes = 14) and has highest observed frequency in the European (Finnish) population (AF= 0.0109111; MAF= 1.09111%, 274/25112 alleles, homozygotes = 2); grpmax FAF= 0.00849119.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.79%
· 12777 / 1,614,156
72 hom · FAF 0.88%
72 hom · FAF 0.88%
Amish 32 / 910 |
3.5% 2 hom |
European (Finnish) 637 / 64,034 |
0.99% 5 hom |
European (non-Finnish) 10600 / 1,180,014 |
0.9% 51 hom |
Remaining individuals 451 / 62,504 |
0.72% 1 hom |
Middle Eastern 42 / 6,062 |
0.69% 1 hom |
South Asian 594 / 91,086 |
0.65% 11 hom |
Ashkenazi Jewish 136 / 29,604 |
0.46% |
Admixed American 197 / 60,008 |
0.33% 1 hom |
African/African American 88 / 75,044 |
0.12% |
+ 1 not observed (East Asian)
gnomAD v2.1
0.65%
· 1825 / 282,158
14 hom · FAF 0.85%
14 hom · FAF 0.85%
European (Finnish) 274 / 25,112 |
1.1% 2 hom |
European (non-Finnish) 1124 / 128,854 |
0.87% 6 hom |
South Asian 212 / 30,594 |
0.69% 5 hom |
Remaining individuals 46 / 7,190 |
0.64% 1 hom |
Ashkenazi Jewish 42 / 10,358 |
0.41% |
Admixed American 94 / 35,348 |
0.27% |
African/African American 33 / 24,778 |
0.13% |
+ 1 not observed (East Asian)
ClinVar
This variant has been reported in ClinVar as Benign (30 clinical laboratories) and as Likely benign (10 clinical laboratories) and as Uncertain significance (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 = 0.07).
Functional
Inconclusive
OncoKB classifies this variant as Inconclusive; biological effect: Inconclusive.
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; COSV66337127, n = 18 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links