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LYFE SCIENCES
Project: HERA
NM_007294.4:c.2155A>G
p.Lys719Glu  ·  BRCA1
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

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.

PMID:31853058 ↗ cspec ↗
4

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.

cspec ↗
5

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.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
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Gaps remaining
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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.
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
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).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueK719
Hotspots ↗