The BRCA2 c.831T>G (p.Asn277Lys) variant has been reported in ClinVar and is classified as Benign by the ClinGen ENIGMA BRCA1/2 expert panel.1 This variant is present in population databases, including gnomAD v2.1 at AF 0.0000687 with a highest observed filter allele frequency of 0.0001033 and gnomAD v4.1 at AF 0.0001886 with a highest observed filter allele frequency of 0.0002296, supporting BS1.2 Calibrated functional data in the ENIGMA BRCA1/2 specification support no damaging effect on protein function for p.(Asn277Lys), supporting BS3.3 In silico evidence does not suggest splice disruption, with a SpliceAI maximum delta score of 0.00, and the missense change lies outside the BRCA2 clinically important domains used by ENIGMA for missense interpretation, supporting BP1_Strong.4
Final classification
Benign
BS1BS3BP1BP6
BRCA2
c.831T>G
p.Asn277Lys
This variant
The BRCA2 c.831T>G (p.Asn277Lys) variant has been reported in ClinVar and is classified as Benign by the ClinGen ENIGMA BRCA1/2 expert panel.
Official ClinGen/ENIGMA BRCA1/2 final-classification framework used: ENIGMA BRCA1 and BRCA2 Specification v1.2, Table 3 criteria-combination rules via the final_classification_framework override.
Classification rationale
BS1BS3BP1BP6
Benign
BRCA2 c.831T>G
BS1 + BS3 + BP1 + 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 · 12 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
BS1
strong
Benign
This variant is present in gnomAD at a frequency above the ENIGMA BS1 strong threshold. In gnomAD v2.1, the highest observed filter allele frequency is 0.0001033 in the European (non-Finnish) population, which is above the BS1 strong threshold of 0.0001.
gnomAD v2.1 grpmax FAF 0.0001033gnomAD v4.1 grpmax FAF 0.0002296
BS3
strong
Benign
Calibrated functional evidence supports no damaging effect. ENIGMA Table 9 lists c.831T>G (p.(Asn277Lys)) as BS3 Strong because one calibrated study found protein function similar to benign control variants.
ENIGMA Table 9 assignment: BS3 StrongReported as similar to benign controls in one calibrated study
BP1
strong
Benign
This missense variant affects codon 277, which is outside the BRCA2 clinically important domains used by ENIGMA for missense interpretation (PALB2-binding aa 10-40 and DNA-binding aa 2481-3186), and SpliceAI predicts no splice effect with a max delta score of 0.00, which is at or below the BP1 threshold of 0.10. This supports BP1_Strong.
Residue 277 is outside aa 10-40 and aa 2481-3186SpliceAI max delta score 0.00
Assessed · not applied
· 4 not met · 8 not assessed
Pathogenic
PS1
No evidence was identified showing that this variant produces the same protein change or the same proven splicing effect as a previously established pathogenic BRCA2 variant.
PS3
Available calibrated functional evidence does not support a damaging effect.
PS4
No standalone case-control evidence was identified showing that this variant is significantly enriched in affected individuals compared with controls at the ENIGMA PS4 threshold.
PM2
This variant is not absent from population databases.
PM3
No evidence was identified of this variant occurring with another BRCA2 variant in a patient with phenotype consistent with BRCA2-related Fanconi anemia, so PM3 cannot be assessed.
PP1
No quantitative co-segregation data were identified showing that this variant tracks with disease in affected relatives, so PP1 cannot be applied.
PP3
Available predictive evidence does not support a damaging effect under the BRCA2 ENIGMA PP3 rule.
PP4
No qualifying multifactorial clinical-history likelihood ratio was identified for this variant, so PP4 cannot be applied.
Benign
BA1
The population frequency does not meet the ENIGMA BA1 threshold.
BS2
No data were identified showing this variant in individuals without features of BRCA2-related Fanconi anemia in a way that permits ENIGMA BS2 point assignment.
BS4
No quantitative non-segregation analysis was identified showing lack of segregation with disease at an ENIGMA BS4 likelihood ratio threshold.
BP5
No qualifying multifactorial clinical-history likelihood ratio in the benign direction was identified for this variant, so BP5 cannot be applied.
N/A · 12
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · 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= 0.000188639; MAF= 0.01886%, 303/1606240 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000253241; MAF= 0.02532%, 298/1176744 alleles, homozygotes = 0); grpmax FAF= 0.0002296.
v2.1
This variant is present in gnomAD v2.1 (AF= 6.87096e-05; MAF= 0.00687%, 19/276526 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000149258; MAF= 0.01493%, 19/127296 alleles, homozygotes = 0); grpmax FAF= 0.0001033.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.019%
· 303 / 1,606,240
0 hom · FAF 0.023%
0 hom · FAF 0.023%
European (non-Finnish) 298 / 1,176,744 |
0.025% |
Remaining individuals 4 / 62,198 |
0.0064% |
African/African American 1 / 74,526 |
0.0013% |
+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0069%
· 19 / 276,526
0 hom · FAF 0.01%
0 hom · FAF 0.01%
European (non-Finnish) 19 / 127,296 |
0.015% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Likely benign (13 clinical laboratories) and as Benign (5 clinical laboratories) and as Uncertain significance (5 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 = 0.00).
Functional
Unknown Oncogenic Effect
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
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.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID 33293522
Found
Structured finding pending for this record — see source link.
Applied to
→BS3
strong
Sources & reference links