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LYFE SCIENCES
Project: HERA
NM_007294.3:c.2155A>G
p.Lys719Glu  ·  BRCA1
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Classification rationale
1

The BRCA1 NM_007294.3:c.2155A>G (NP_009225.1:p.(Lys719Glu), NP_009225.1:p.(K719E)) variant has not been observed in COSMIC and has been reported in ClinVar with a current expert-panel Benign classification, although older laboratory submissions include uncertain significance and likely benign assertions.

clinvar ↗
2

This variant is present in population databases, including gnomAD v2.1 and v4.1, with grpmax FAF values of 0.00062195 and 0.00068503, respectively, which are above the ENIGMA BS1 threshold of 0.0001 but below the BA1 threshold of 0.001.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

Multifactorial clinical-history evidence is in the benign direction, with a BRCA1 clinical-history likelihood ratio of 0.0137 from 10 probands, meeting BP5_Strong and arguing against pathogenicity.

PMID:31853058 ↗ cspec ↗
4

In silico evidence does not support a damaging effect in the ENIGMA BRCA1 framework: SpliceAI predicts no splice impact (max delta score 0.00), BayesDel is -0.216062, and the missense change lies outside the BRCA1 domains used for PP3/BP4, supporting BP1_Strong rather than 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
  • —
Gaps remaining
  • —
Rule
—
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). (ClinVarID = 37452)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. 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). REVEL score = 0.404. BayesDel score = -0.216062.
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 ↗