The BRCA2 c.7977-1G>C (p.?) variant has been reported in ClinVar as pathogenic, including review by the ClinGen ENIGMA BRCA1/2 expert panel.1 This variant is present at very low frequency in population databases, with 2/281032 alleles in gnomAD v2.1 (AF 7.12e-06) and 5/1612350 alleles in gnomAD v4.1 (AF 3.10e-06; grpmax FAF 1.24e-06), which is too low for BS1 or BA1 but means PM2 is not met because the variant is not absent from controls.2 A BRCA2 clinical-history likelihood-ratio analysis reported LR 7.22 across 7 probands, which meets ENIGMA PP4_Moderate.3 RNA evidence cited by ENIGMA indicates that variants at this splice acceptor site cause leaky abnormal splicing, and ENIGMA specifically assigns c.7977-1G>C as PVS1_Strong (RNA).4 SpliceAI predicts a strong splice effect for this variant with a maximum delta score of 0.95, which supports splice disruption but is not separately counted as PP3 because the variant is at a canonical splice position already captured by PVS1.5
BRCA2
Final classification
Likely Pathogenic
BRCA2 c.7977-1G>C · p.?
BRCA2
The BRCA2 c.7977-1G>C (p.?) variant has been reported in ClinVar as pathogenic, including review by the ClinGen ENIGMA BRCA1/2 expert panel.
ClinGen ENIGMA BRCA1/BRCA2 Specification v1.2.0 final-classification framework using Table 3 criteria-combination rules from the official CSPEC/VCEP framework.
Classification rationale
PP4PVS1PP5
Likely Pathogenic
BRCA2 c.7977-1G>C
PP4 + PVS1 + PP5
→
Likely Pathogenic
3
PMID:31853058 ↗vcep_pmid_31853058_brca2_clinical_history_lrvcep_specifications_v1_2_2024_11_18
4
vcep_specifications_table4_v1_2_2024_11_18vcep_humu_40_1557_s001PMID:16211554 ↗
5
spliceai ↗pvs1_variant_assessmentcspec ↗
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 3 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 · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.10106e-06; MAF= 0.00031%, 5/1612350 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.2405e-06; MAF= 0.00042%, 5/1179106 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 7.11663e-06; MAF= 0.00071%, 2/281032 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.56023e-05; MAF= 0.00156%, 2/128186 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00031%
· 5 / 1,612,350
0 hom · FAF 0.00012%
0 hom · FAF 0.00012%
European (non-Finnish) 5 / 1,179,106 |
0.00042% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.00071%
· 2 / 281,032
0 hom
0 hom
European (non-Finnish) 2 / 128,186 |
0.0016% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Pathogenic (20 clinical laboratories) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.95).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV104701362, n = 1 times).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Literature · how each cited paper was used
7papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID PMID:16211554
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1 supports · met
PMID PMID:31853058
Found
Structured finding pending for this record — see source link.
Applied to
→PP4 supports · met
PMID cspec
Found
Structured finding pending for this record — see source link.
Applied to
→PP5 supports · met
→PVS1 supports · met
PMID vcep_humu_40_1557_s001
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1 supports · met
PMID vcep_pmid_31853058_brca2_clinical_history_lr
Found
Structured finding pending for this record — see source link.
Applied to
→PP4 supports · met
PMID vcep_specifications_table4_v1_2_2024_11_18
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1 supports · met
PMID vcep_specifications_v1_2_2024_11_18
Found
Structured finding pending for this record — see source link.
Applied to
→PP4 supports · met
Sources & reference links