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
Final classification
Uncertain Significance
PS3PP5
BRCA2
c.7879A>T
p.Ile2627Phe
This variant
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
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Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
PS3
strong
Pathogenic
This variant has calibrated functional evidence showing a damaging effect on BRCA2 protein function. ENIGMA Table 9 assigns PS3 Strong for c.7879A>T (p.Ile2627Phe), with three calibrated studies reported as supportive of abnormal protein function.
ENIGMA Table 9 row for BRCA2 c.7879A>T / p.(Ile2627Phe): PS3 StrongTable 9 notes three calibrated studies supportive of damaging protein functionOncoKB lists the variant as Likely Oncogenic with loss-of-function effect
Assessed · not applied
· 9 not met · 9 not assessed
Pathogenic
PVS1
This variant is a missense substitution, not a nonsense, frameshift, canonical splice-site, initiation-codon, or exon-level loss-of-function variant, so PVS1 is not met for this BRCA2 change.
PS1
No same-amino-acid pathogenic comparison variant was identified in the retrieved evidence, so PS1 was not independently assessed.
PS4
This variant has been reported in ClinVar and once in COSMIC, and ENIGMA supplementary material lists a posterior pathogenicity of 0.9977 with IARC class 5.
PM2
This variant is absent from gnomAD v2.1 but present in gnomAD v4.1 at 4/1,614,168 alleles (AF 2.47806e-06; 0 homozygotes), so it is not absent from control datasets and PM2 is not met.
PM3
No evidence was identified for biallelic BRCA2 disease, Fanconi anemia phenotype, or a qualifying in-trans co-occurring BRCA2 pathogenic variant, so PM3 was not assessed.
PM5
No qualifying alternate pathogenic missense variant at the same codon was identified in the retrieved evidence, and the exon-level PM5_PTC framework is for protein-truncating variants rather than this missense substitution, so PM5 was not assessed.
PP1
No quantitative co-segregation likelihood ratio was identified, so PP1 was not assessed.
PP3
This missense variant lies within the BRCA2 DNA-binding domain, but SpliceAI predicts no significant splice effect (max delta score 0.07, below the PP3 splice threshold of 0.2).
PP4
The BRCA2 clinical-history likelihood ratio for this variant is 0.68 from 3 probands, which is below the PP4 Supporting threshold of 2.08, so PP4 is not met.
Benign
BA1
The gnomAD v4.1 grpmax filter allele frequency is 7.9e-07, which is below the BA1 threshold of 0.001 (0.1%), so BA1 is not met.
BS1
The gnomAD v4.1 grpmax filter allele frequency is 7.9e-07, which is below the BS1 Supporting threshold of 0.00002 and well below the BS1 Strong threshold of 0.0001, so BS1 is not met.
BS2
No qualifying observations of this variant in individuals without Fanconi anemia features were identified for BRCA2 BS2 scoring, so BS2 was not assessed.
BS3
Available calibrated functional evidence does not show normal BRCA2 protein function.
BS4
No quantitative lack-of-segregation likelihood ratio was identified, so BS4 was not assessed.
BP1
This missense variant is within the BRCA2 DNA-binding domain (amino acids 2481-3186), so it does not meet the BP1 requirement for a missense or silent variant outside a clinically important domain.
BP4
SpliceAI predicts no significant splice impact (max delta score 0.07, within the BP4 splice threshold of 0.1), and the variant is within the BRCA2 DNA-binding domain.
BP5
The BRCA2 clinical-history likelihood ratio for this variant is 0.68 from 3 probands, which is above the BP5 Supporting threshold of 0.48, so BP5 is not met.
BP7
Although mRNA evidence in ENIGMA Table 9 notes no aberration and SpliceAI is low at 0.07, this is a missense variant within the BRCA2 DNA-binding domain, and BRCA2 BP7 for missense variants in a clinically important domain requires BS3 to be met.
N/A · 8
PS2 · PM1 · PM4 · PM6 · PP2 · BP2 · BP3 · BP6
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