LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-04-26
Case ID: NM_000059.4_c.7977-1G_C_20260426_035651
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.4:c.7977-1G>C

BRCA2  · NP_000050.3:p.?  · NM_000059.4
GRCh37: chr13:32937315 G>C  ·  GRCh38: chr13:32363178 G>C
Gene: BRCA2 Transcript: NM_000059.4
Final call
Likely Pathogenic
PVS1_Strong PP4_Moderate PP5_Supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA2
Transcript
NM_000059.4
Protein
NP_000050.3:p.?
gnomAD AF
ClinVar
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
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.
2
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.
3
A BRCA2 clinical-history likelihood-ratio analysis reported LR 7.22 across 7 probands, which meets ENIGMA PP4_Moderate.
4
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).
5
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.
Final determination: Likely pathogenic based on PVS1_Strong and PP4_Moderate under ENIGMA Table 3; PP5_Supporting is concordant additional evidence and is not required for the final call.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
BP4 Not met This canonical splice acceptor variant is not eligible for BP4 because SpliceAI predicts splice disruption with a max delta score of 0.95, which is above the ENIGMA no-impact threshold of 0.1.
spliceai cspec vcep_specifications_v1_2_2024_11_18
PP1 Not assessed No quantitative co-segregation data were identified, so PP1 cannot be assessed.
cspec vcep_specifications_v1_2_2024_11_18
BS1 Not met Population frequency does not meet ENIGMA BS1 thresholds. In gnomAD v4.1 the grpmax FAF is 1.24e-06, which is below the Supporting threshold of 2.0e-05 and below the Strong threshold of 1.0e-04.
gnomad_v4 gnomad_v2 cspec
PM3 Not assessed No evidence was identified for biallelic occurrence with a BRCA2-related Fanconi anemia phenotype, so PM3 cannot be assessed.
cspec vcep_specifications_v1_2_2024_11_18
PM2 Not met This variant is not absent from population databases. It is present in gnomAD v2.1 at 2/281032 alleles (AF 7.12e-06) and in gnomAD v4.1 at 5/1612350 alleles (AF 3.10e-06), so ENIGMA PM2 is not met.
gnomad_v2 gnomad_v4 cspec
PP4 Met A BRCA2 clinical-history likelihood-ratio analysis reported this variant in 7 probands with LR 7.22, which is above the ENIGMA PP4 Moderate threshold of 4.3 and below the Strong threshold of 18.7.
PMID:31853058 vcep_pmid_31853058_brca2_clinical_history_lr vcep_specifications_v1_2_2024_11_18
BP3 N/A BP3 is not applicable in the ENIGMA BRCA2 specification.
cspec
PVS1 Met This canonical splice acceptor variant affects BRCA2 c.7977-1, a site where loss of function is an established disease mechanism. ENIGMA Table 4 specifically assigns c.7977-1G>C as PVS1_Strong (RNA) because variants at this splice site are reported to cause leaky abnormal splicing, so full-strength PVS1 is reduced to Strong.
cspec pvs1_gene_context pvs1_variant_assessment vcep_specifications_table4_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:16211554
PM1 N/A PM1 is not applicable in the ENIGMA BRCA2 specification for this type of splice-site variant.
cspec
PP5 Met Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.
cspec clinvar
BS2 Not assessed No BRCA2-specific BS2 point-based evidence was identified, and this variant was not observed as a homozygote in gnomAD, so BS2 cannot be assessed.
gnomad_v2 gnomad_v4 cspec
BP1 Not met BP1 is not met because this is a canonical splice-site variant with predicted splice disruption, not a silent, missense, or in-frame variant outside a critical domain with no predicted splice impact.
spliceai cspec
BS4 Not assessed No quantitative lack-of-segregation data were identified, so BS4 cannot be assessed.
cspec vcep_specifications_v1_2_2024_11_18
BS3 Not met Available functional evidence does not support BS3. Reported RNA studies indicate abnormal splicing, and ENIGMA routes damaging mRNA-only evidence to PVS1(RNA) rather than BS3.
vcep_humu_40_1557_s001 vcep_specifications_v1_2_2024_11_18 PMID:16211554
PS1 Not assessed No criterion-ready ENIGMA PS1 comparison variant with the same established splice effect was identified from the reviewed materials, so PS1 was not applied.
cspec vcep_specifications_v1_2_2024_11_18
BP7 Not met BP7 is not met because this variant is at a canonical -1 splice position and available RNA data support abnormal splicing rather than no impact on the transcript.
spliceai vcep_humu_40_1557_s001 cspec
BA1 Not met Population frequency is far below the ENIGMA BA1 threshold. In gnomAD v4.1 the grpmax FAF is 1.24e-06, which is below the BA1 threshold of 0.001.
gnomad_v4 gnomad_v2 cspec
PM5 Not assessed BRCA2 exon 18 is a PM5_PTC-applicable exon in ENIGMA Table 4, but a clear criterion-ready PM5 assignment was not identified for this leaky splice variant independent of the PVS1(RNA) assessment, so PM5 was not applied in this pass.
vcep_specifications_table4_v1_2_2024_11_18 cspec
BP5 Not met The BRCA2 clinical-history likelihood ratio is 7.22, which is above 2.08 and therefore supports pathogenicity rather than benignity. This is above the ENIGMA BP5 benign thresholds of 0.48, 0.23, and 0.05.
PMID:31853058 vcep_pmid_31853058_brca2_clinical_history_lr vcep_specifications_v1_2_2024_11_18
PS3 Not met Available functional evidence is based on RNA splicing studies rather than protein-function assays, and ENIGMA directs damaging mRNA-only evidence to PVS1(RNA) instead of PS3.
vcep_humu_40_1557_s001 vcep_specifications_v1_2_2024_11_18 PMID:16211554 PMID:20020529
PM6 N/A PM6 is not applicable in the ENIGMA BRCA2 specification.
cspec
PS4 Not assessed This variant has been observed in affected individuals, but no case-control analysis with p-value 0.05 or lower and odds ratio 4 or higher was identified, so PS4 cannot be assigned from the reviewed evidence.
clinvar vcep_humu_40_1557_s001 cspec
PM4 N/A PM4 is not applicable in the ENIGMA BRCA2 specification.
cspec
BP6 N/A BP6 is not applicable in the ENIGMA BRCA2 specification.
cspec
PS2 N/A PS2 is not applicable in the ENIGMA BRCA2 specification.
cspec
PP3 N/A PP3 is not applied for this canonical +/-1 splice variant. ENIGMA PP3 for intronic variants is directed to sites outside the donor and acceptor 1,2 positions, and the generic PVS1 framework also advises against stacking PP3 on the same splice prediction evidence.
spliceai cspec pvs1_variant_assessment
PP2 N/A PP2 is not applicable in the ENIGMA BRCA2 specification.
cspec
BP2 N/A BP2 is not applicable in the ENIGMA BRCA2 specification.
cspec
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