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.1 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 PM2.2 Calibrated functional evidence supports a damaging effect on BRCA2 protein function, and ENIGMA Table 9 assigns PS3 Strong for c.7879A>T (p.Ile2627Phe).3 The variant lies within the BRCA2 DNA-binding domain, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.07.4
BRCA2
Final classification
Uncertain Significance
BRCA2 c.7879A>T · p.Ile2627Phe
BRCA2
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.
Official ClinGen ENIGMA BRCA1 and BRCA2 Specification v1.2 Table 3 final-classification combination rules were used as the primary CSPEC/VCEP framework.
Classification rationale
PS3PP5
Uncertain Significance
BRCA2 c.7879A>T
PS3 + PP5
→
Uncertain Significance
3
vcep_specifications_table9_v1_2_2024_11_18
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 2 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
gnomAD v4.1
gnomAD v2.1
v4.1
This 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.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00025%
· 4 / 1,614,168
0 hom · FAF 7.9e-05%
0 hom · FAF 7.9e-05%
European (non-Finnish) 4 / 1,180,020 |
0.00034% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).
Functional
Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Loss-of-function.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
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).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links