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
Final classification
Pathogenic
PVS1PM5PP4PP5
BRCA2
c.7977-1G>C
p.?
This variant
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
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 12 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 · 4
Strength
Supporting
Moderate
Strong
Very strong
PVS1
strong
Pathogenic
This canonical splice acceptor variant in BRCA2 exon 18 is assigned PVS1_Strong (RNA) by the ENIGMA BRCA2 specification. ENIGMA notes that variants at this splice site show leaky splicing, which reduces the weight from very strong to strong; RNA evidence summarized for this variant shows exon 18 deletion and exon 17/18 deletion, supporting an abnormal loss-of-function transcript effect.
BRCA2 loss of function is an established disease mechanism in the ENIGMA framework.ENIGMA Table 4 lists c.7977-1G>C as PVS1_Strong (RNA) with reduced strength because of leaky splicing at this site.Splicing evidence summarized for this variant includes exon 18 deletion and exon 17/18 deletion.
PM5
strong
Pathogenic
ENIGMA BRCA2 Table 4 designates exon 18 as eligible for PM5_Strong (PTC). Because this canonical splice variant is assigned PVS1 at exon 18 and ENIGMA applies PM5_PTC at this exon, additional strong pathogenic weight is supported.
ENIGMA Table 4 lists exon 18 with PM5_Strong (PTC) applicability.The variant is a canonical splice variant at the exon 18 acceptor.
PP4
moderate
Pathogenic
In the BRCA2 clinical-history likelihood-ratio dataset, this variant has an LR of 7.223 across 7 probands. This exceeds the ENIGMA PP4_Moderate threshold of 4.3 and is below the PP4_Strong threshold of 18.7, supporting PP4 at moderate strength.
Clinical-history LR 7.223215162037175.N probands = 7.PP4_Moderate threshold >= 4.3
Assessed · not applied
· 6 not met · 6 not assessed
Pathogenic
PS1
No independently reviewed pathogenic comparator variant with the same established splicing effect was identified to support PS1.
PS3
Available functional evidence is RNA splicing evidence rather than a qualifying protein functional assay.
PS4
This variant has been reported in affected individuals, but no qualifying case-control analysis with an odds ratio and confidence interval meeting the ENIGMA PS4 threshold was identified.
PM2
This variant is not absent from population databases.
PM3
No data were identified showing this variant in trans with another pathogenic BRCA2 variant in an individual with a phenotype consistent with BRCA2-related Fanconi anemia.
PP1
No quantitative segregation data were identified for this variant.
Benign
BA1
The observed population frequency is far below the ENIGMA BA1 threshold.
BS1
The observed population frequency is below the ENIGMA BS1 thresholds.
BS2
No evidence was identified showing this variant in individuals scored under the ENIGMA BS2 recessive-disease framework.
BS3
No functional evidence showing normal transcript or normal BRCA2 function was identified for this variant.
BS4
No quantitative non-segregation data were identified for this variant.
BP5
The clinical-history likelihood ratio does not support BP5.
N/A · 12
PS2 · PM1 · PM4 · PM6 · PP2 · PP3 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7
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.
Molecular characterization and cancer risk associated with BRCA1 and BRCA2 splic
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1
strong
Li et al. 2020 BRCA1/2 clinical-history likelihood-ratio model
Found
Structured finding pending for this record — see source link.
Applied to
→PP4
moderate
Sources & reference links