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
BRCA1
Final classification
Benign
BRCA1 c.2155A>G · p.Lys719Glu
BRCA1
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 ↗
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
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= 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.
PMID PMID:31853058
Found
Structured finding pending for this record — see source link.
Applied to
→BP5 supports · met
Sources & reference links