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LYFE SCIENCES
Project: HERA
NM_000059.4:c.7879A>T
p.Ile2627Phe  ·  BRCA2
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Classification rationale
1

The BRCA2 c.7879A>T (p.Ile2627Phe) variant has been observed in somatic cancer once in COSMIC and has been reported in ClinVar as Pathogenic, including review by the ClinGen ENIGMA BRCA1/2 expert panel.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 at 4/1614168 alleles (AF 2.47806e-06; 0 homozygotes; grpmax FAF 7.9e-07), which is well below benign population thresholds but does not satisfy ENIGMA absence-based PM2.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

Calibrated functional evidence supports a damaging effect on BRCA2 protein function, and ENIGMA Table 9 assigns PS3 Strong for c.7879A>T (p.Ile2627Phe).

4

The variant lies within the BRCA2 DNA-binding domain, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.07.

cspec ↗ spliceai ↗
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 v2.1Absent from gnomAD v2.1.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 2.47806e-06; MAF= 0.00025%, 4/1614168 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.38977e-06; MAF= 0.00034%, 4/1180020 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (20 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Loss-of-function.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV107497848, n = 1 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueI2627
Hotspots ↗