The BRCA2 c.7977-1G>C (p.?) variant has been reported in ClinVar as Pathogenic, including a Pathogenic expert-panel classification from ENIGMA.1 This variant is present at a very low frequency in population databases, with gnomAD v2.1 AF 7.11663e-06 (2/281032 alleles) and gnomAD v4.1 AF 3.10106e-06 (5/1612350 alleles), which is below benign frequency thresholds.2 RNA studies summarized in the ENIGMA BRCA2 materials reported abnormal splicing for this variant, including exon 18 deletion and exon 17/18 deletion, and ENIGMA Table 4 assigns PVS1_Strong (RNA) at this splice acceptor because variants at this site show leaky splicing.3 Computational splicing analysis is also strongly abnormal, with a SpliceAI maximum delta score of 0.95, consistent with splice disruption, although this prediction is not counted separately because splice-impact evidence is already captured under PVS1 in the ENIGMA framework.4 In the BRCA2 clinical-history likelihood-ratio dataset, this variant had an LR of 7.223 across 7 probands, which meets the ENIGMA threshold for PP4 at moderate strength.5
BRCA2
Final classification
Pathogenic
BRCA2 c.7977-1G>C · p.?
BRCA2
The BRCA2 c.7977-1G>C (p.?) variant has been reported in ClinVar as Pathogenic, including a Pathogenic expert-panel classification from ENIGMA.
ENIGMA BRCA1/BRCA2 Specification v1.2.0 final-classification framework (Table 3 criteria-combination rules via CSPEC/VCEP override).
Classification rationale
PVS1PM5PP4PP5
Pathogenic
BRCA2 c.7977-1G>C
PVS1 + PM5 + PP4 + PP5
→
Pathogenic
3
vcep_humu_40_1557_s001vcep_specifications_table4_v1_2_2024_11_18PMID:16211554 ↗
4
spliceai ↗cspec ↗pvs1_variant_assessment
5
vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗vcep_specifications_v1_2_2024_11_18
Gene diagram
· NM_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 4 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). BayesDel score = 0.308409.
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
2papers 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
Sources & reference links