The BRCA1 c.2155A>G (p.Lys719Glu; p.K719E) variant has been reported in ClinVar, where the ClinGen ENIGMA BRCA1 and BRCA2 expert panel classified it as benign.1 This variant is present in gnomAD v2.1 and v4.1, with grpmax filter allele frequencies of 0.00062195 and 0.00068503, respectively, both above the ENIGMA BS1 strong threshold of 0.0001 and below the BA1 threshold of 0.001.2 A BRCA1 clinical-history likelihood ratio of 0.0137 from 10 probands is below the ENIGMA BP5_Strong threshold of 0.05, supporting evidence against pathogenicity.3 No variant-specific damaging or benign functional result for c.2155A>G (p.Lys719Glu) was identified in the reviewed ENIGMA functional assay resources, so PS3 and BS3 were not assessed.4 The p.Lys719Glu change lies outside the BRCA1 RING, coiled-coil, and BRCT domains defined by ENIGMA, and SpliceAI predicts no splice impact with a maximum delta score of 0.00, supporting BP1_Strong and not supporting PP3.5
Final classification
Benign
BS1BP1BP5BP6
BRCA1
c.2155A>G
p.Lys719Glu
This variant
The BRCA1 c.2155A>G (p.Lys719Glu; p.K719E) variant has been reported in ClinVar, where the ClinGen ENIGMA BRCA1 and BRCA2 expert panel classified it as benign.
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework (CSPEC/VCEP official framework override).
Classification rationale
BS1BP1BP5BP6
Benign
BRCA1 c.2155A>G
BS1 + BP1 + BP5 + BP6
→
Benign
3
vcep_pmid_31853058_brca1_clinical_history_lrPMID:31853058 ↗cspec ↗
4
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18cspec ↗
5
vcep_appendices_v1_2_2024_11_18spliceai ↗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_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 4 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 · 4
Strength
Supporting
Moderate
Strong
Very strong
BS1
strong
Benign
This variant exceeds the ENIGMA BS1 strong threshold for population frequency. The highest observed grpmax FAF is 0.00062195 in gnomAD v2.1 and 0.00068503 in gnomAD v4.1, both above the BS1 strong cutoff of 0.0001 and below the BA1 cutoff of 0.001.
gnomAD v2.1 grpmax FAF = 0.00062195 in African/African American individuals.gnomAD v4.1 grpmax FAF = 0.00068503 in African/African American individuals.
BP1
strong
Benign
This missense variant is outside the BRCA1 clinically important functional domains used by ENIGMA, and SpliceAI predicts no splice effect with a maximum delta score of 0.00, which is below the BP1 splice threshold of 0.10. These findings meet BP1_Strong.
Protein change is p.(Lys719Glu) at amino acid 719.BRCA1 clinically important domains are aa 2-1011391-1424
BP5
strong
Benign
The BRCA1 clinical-history likelihood ratio for this variant is 0.0137 from 10 probands, which is below the BP5_Strong threshold of 0.05. This provides strong evidence against pathogenicity under the ENIGMA multifactorial clinical-data framework.
BRCA1 c.2155A>G clinical-history LR = 0.01373116940682096.N_Probands = 10.
Assessed · not applied
· 6 not met · 9 not assessed
Pathogenic
PVS1
This missense variant does not fall into the BRCA1 loss-of-function categories used for PVS1.
PS1
No previously classified pathogenic or likely pathogenic variant with the same established amino acid or splice effect was identified in the reviewed evidence, so PS1 was not assessed.
PS3
No variant-specific damaging functional result for c.2155A>G (p.Lys719Glu) was identified in the reviewed ENIGMA functional resources, so PS3 was not assessed.
PS4
No case-control study or quantitative prevalence analysis showing a significant enrichment of this variant in affected individuals was identified, so PS4 was not assessed.
PM1
This variant is outside the BRCA1 clinically important functional domains defined by ENIGMA, and no hotspot evidence was identified.
PM2
This variant is not absent from population databases.
PM3
No evidence was identified that this variant was observed in trans with another BRCA1 variant in an individual with BRCA1-related Fanconi anemia, so PM3 was not assessed.
PP1
No quantitative co-segregation data were identified for this variant, so PP1 was not assessed.
PP3
Available predictive evidence does not meet the ENIGMA PP3 thresholds.
PP4
The available BRCA1 clinical-history likelihood ratio is 0.0137 from 10 probands, which is well below the PP4 pathogenic threshold of 2.08.
Benign
BA1
The filter allele frequency does not reach the ENIGMA BA1 threshold.
BS2
No qualifying observations in unaffected individuals were identified for the ENIGMA BRCA1 BS2 points-based framework, so BS2 was not assessed.
BS3
No variant-specific benign functional result for c.2155A>G (p.Lys719Glu) was identified in the reviewed ENIGMA functional resources, so BS3 was not assessed.
BS4
No quantitative lack-of-segregation data were identified for this variant, so BS4 was not assessed.
BP7
No qualifying RNA study showing no damaging effect on transcript processing was identified for this missense variant, so BP7 was not assessed.
N/A · 9
PS2 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP4
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.15102e-05; MAF= 0.00415%, 67/1614060 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000852583; MAF= 0.08526%, 64/75066 alleles, homozygotes = 0); grpmax FAF= 0.00068503.
v2.1
This variant is present in gnomAD v2.1 (AF= 7.0823e-05; MAF= 0.00708%, 20/282394 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000803277; MAF= 0.08033%, 20/24898 alleles, homozygotes = 0); grpmax FAF= 0.00062195.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0042%
· 67 / 1,614,060
0 hom · FAF 0.069%
0 hom · FAF 0.069%
African/African American 64 / 75,066 |
0.085% |
Remaining individuals 3 / 62,506 |
0.0048% |
+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish))
gnomAD v2.1
0.0071%
· 20 / 282,394
0 hom · FAF 0.062%
0 hom · FAF 0.062%
African/African American 20 / 24,898 |
0.08% |
+ 7 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories) and as Likely benign (7 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: BRCA1, 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.
Li et al. 2020 BRCA1/2 clinical-history likelihood-ratio model
Found
Structured finding pending for this record — see source link.
Applied to
→BP5
strong
Sources & reference links