LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-04-30
Case ID: NM_000059.3_c.7759C_T_20260430_143410
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.3:c.7759C>T

BRCA2  · NP_000050.2:p.(Leu2587Phe)  · NM_000059.3
GRCh37: chr13:32932020 C>T  ·  GRCh38: chr13:32357883 C>T
Gene: BRCA2 Transcript: NM_000059.3
Final call
Likely Benign
BS1_Supporting BS3_Strong BP4_Supporting BP6_Supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA2
Transcript
NM_000059.3
Protein
NP_000050.2:p.(Leu2587Phe)
gnomAD AF
ClinVar
OncoKB
Likely Neutral
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The BRCA2 c.7759C>T (p.Leu2587Phe; p.L2587F) variant has been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 Variant Curation Expert Panel classifies it as benign.
2
This variant is present in gnomAD v2.1 and v4.1, with grpmax filter allele frequencies of 4.115e-05 and 4.535e-05, respectively; these values are above the ENIGMA BRCA2 BS1 Supporting threshold of 2.0e-05 and below the BS1 Strong threshold of 1.0e-04.
3
In calibrated functional studies curated by the ENIGMA BRCA2 specification, this variant showed protein function similar to benign control variants, supporting BS3 at Strong strength.
4
Computational evidence does not support a damaging effect under the ENIGMA BRCA2 rule because the BayesDel no-AF score is 0.147986 and the SpliceAI maximum delta score is 0.04, meeting BP4 thresholds for no predicted impact; REVEL is 0.73 but is not the operative ENIGMA BRCA2 threshold for this rule.
Final determination: ENIGMA BRCA1/2 Table 3 supports a Likely Benign classification because one strong benign criterion (BS3) and supporting benign criteria (BS1, BP4, and BP6) are met.
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
PVS1 N/A This variant is a missense substitution, p.(Leu2587Phe), and available data do not show a predicted or demonstrated loss-of-function splicing effect. SpliceAI shows a maximum delta score of 0.04, below the ENIGMA BRCA2 splice-prediction thresholds used for PVS1-related consideration.
pvs1_gene_context pvs1_variant_assessment spliceai vcep_specifications_v1_2_2024_11_18
PS1 Not assessed No qualifying evidence was identified showing that this variant has the same protein or splice consequence as a previously classified pathogenic or likely pathogenic BRCA2 variant under the ENIGMA BRCA2 rule.
vcep_specifications_v1_2_2024_11_18 clinvar
PS2 N/A This criterion is not applicable in the ENIGMA BRCA2 specification for this review context.
vcep_specifications_v1_2_2024_11_18
PS3 Not met Available calibrated functional evidence does not support a damaging effect. In the ENIGMA BRCA2 curated functional table, this variant is assigned BS3_Strong rather than PS3 because published assays showed protein function similar to benign control variants.
vcep_specifications_table9_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
PS4 Not assessed No case-control study was identified showing a statistically significant enrichment of this variant in affected individuals compared with controls. Available multifactorial data were neutral rather than clearly supportive of pathogenic enrichment.
vcep_specifications_v1_2_2024_11_18 vcep_humu_40_1557_s001 clinvar
PM1 N/A Although codon 2587 lies within the BRCA2 DNA-binding region, the ENIGMA BRCA2 specification marks PM1 as not applicable for this framework.
vcep_specifications_v1_2_2024_11_18
PM2 Not met This variant is not absent from population controls. It is present in gnomAD v2.1 at 11/251436 alleles (AF 4.37487e-05) and in gnomAD v4.1 at 75/1613928 alleles (AF 4.64705e-05), so the ENIGMA BRCA2 PM2 absence criterion is not met.
gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18
PM3 Not assessed No evidence was identified that this variant was observed with another BRCA2 variant in a patient with a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 could not be evaluated.
vcep_specifications_v1_2_2024_11_18
PM4 N/A This criterion is not applicable in the ENIGMA BRCA2 specification for this review context.
vcep_specifications_v1_2_2024_11_18
PM5 N/A Under the ENIGMA BRCA2 specification, the reviewed PM5 rule is for protein-truncating variants in eligible exons. This variant is a missense substitution and does not meet that rule context.
vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PM6 N/A This criterion is not applicable in the ENIGMA BRCA2 specification for this review context.
vcep_specifications_v1_2_2024_11_18
PP1 Not assessed No quantitative segregation data were identified showing that this variant co-segregates with disease in affected family members, so PP1 could not be applied.
vcep_specifications_v1_2_2024_11_18 clinvar
PP2 N/A This criterion is not applicable in the ENIGMA BRCA2 specification for this review context.
vcep_specifications_v1_2_2024_11_18
PP3 Not met Computational evidence does not meet the ENIGMA BRCA2 PP3 rule. This missense variant lies within the BRCA2 DNA-binding domain, but the BayesDel no-AF score is 0.147986, below the PP3 threshold of 0.30, and SpliceAI shows a maximum delta score of 0.04, below the splice threshold of 0.20. REVEL is 0.73, but the official ENIGMA BRCA2 rule for this criterion uses BayesDel and SpliceAI.
bayesdel spliceai revel vcep_specifications_v1_2_2024_11_18
PP4 Not met The BRCA2 clinical-history likelihood ratio for this variant is 0.5820637473 from 6 probands, which is below the ENIGMA BRCA2 PP4 Supporting threshold of 2.08. This value does not support pathogenic clinical-history enrichment.
vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 vcep_specifications_v1_2_2024_11_18
PP5 N/A This criterion is not applicable in the ENIGMA BRCA2 specification for this review context.
vcep_specifications_v1_2_2024_11_18
BA1 Not met Population frequency does not reach the ENIGMA BRCA2 BA1 threshold. The highest reviewed grpmax FAF is 4.535e-05 in gnomAD v4.1, which is below the BA1 threshold of 0.001.
gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18
BS1 Met This variant meets BS1 at Supporting strength because its filter allele frequency exceeds the ENIGMA BRCA2 BS1 Supporting threshold of 0.00002 but does not exceed the Strong threshold of 0.0001. In gnomAD v2.1, grpmax FAF is 4.115e-05, and in gnomAD v4.1, grpmax FAF is 4.535e-05.
gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18
BS2 Not assessed No qualifying data were identified showing this variant in individuals without features of BRCA2-related Fanconi anemia in a way that would meet the ENIGMA BRCA2 BS2 point-based framework.
vcep_specifications_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS3 Met This variant meets BS3 at Strong strength. In the ENIGMA BRCA2 curated functional assay table, two calibrated studies reported protein function similar to benign control variants, supporting a benign functional interpretation.
vcep_specifications_table9_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
BS4 Not assessed No quantitative lack-of-segregation data were identified showing that this variant fails to track with disease in affected relatives, so BS4 could not be applied.
vcep_specifications_v1_2_2024_11_18 clinvar
BP1 Not met This missense variant does not meet BP1 because codon 2587 is within the BRCA2 DNA-binding domain at amino acids 2481-3186, whereas the ENIGMA BRCA2 BP1 rule is for missense or silent variants outside a clinically important functional domain with no predicted splice effect.
spliceai vcep_specifications_v1_2_2024_11_18
BP2 N/A This criterion is not applicable in the ENIGMA BRCA2 specification for this review context.
vcep_specifications_v1_2_2024_11_18
BP3 N/A This criterion is not applicable in the ENIGMA BRCA2 specification for this review context.
vcep_specifications_v1_2_2024_11_18
BP4 Met This variant meets BP4 at Supporting strength under the ENIGMA BRCA2 computational rule. Codon 2587 is within the BRCA2 DNA-binding domain, BayesDel no-AF is 0.147986, which is at or below the BP4 threshold of 0.18, and SpliceAI shows a maximum delta score of 0.04, which is at or below the BP4 threshold of 0.1. REVEL is 0.73, but the official ENIGMA BRCA2 rule for this criterion uses BayesDel and SpliceAI.
bayesdel spliceai revel vcep_specifications_v1_2_2024_11_18
BP5 Not met The BRCA2 clinical-history likelihood ratio for this variant is 0.5820637473 from 6 probands, which is above the ENIGMA BRCA2 BP5 Supporting threshold of 0.48. This value falls in the neutral zone and does not support a benign clinical-history criterion.
vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 vcep_specifications_v1_2_2024_11_18
BP6 Met Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Benign.
vcep_specifications_v1_2_2024_11_18 clinvar
BP7 N/A This is a missense variant in the BRCA2 DNA-binding domain, and no qualifying RNA-only benign evidence was identified for BP7 application.
spliceai vcep_specifications_v1_2_2024_11_18
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