LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-05-09
Case ID: NM_000059.3_c.7685T_G_20260509_191059
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.3:c.7685T>G

BRCA2  · NP_000050.2:p.(Phe2562Cys)  · NM_000059.3
GRCh37: chr13:32931946 T>G  ·  GRCh38: chr13:32357809 T>G
Gene: BRCA2 Transcript: NM_000059.3
Final call
Likely Pathogenic
PS3_Strong PM2_Supporting PP3_Supporting PP5_Supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA2
Transcript
NM_000059.3
Protein
NP_000050.2:p.(Phe2562Cys)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The BRCA2 c.7685T>G (p.Phe2562Cys; p.F2562C) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 expert panel classifies it as likely pathogenic.
2
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population controls.
3
In a calibrated BRCA2 functional study summarized by the ENIGMA functional assay table, this variant showed protein function similar to pathogenic control variants, supporting PS3_Strong.
4
This missense change lies in the BRCA2 DNA-binding domain; BayesDel no-AF is 0.421539, which is above the ENIGMA PP3 threshold of 0.30, REVEL is 0.921, and SpliceAI predicts little splice effect with a maximum delta score of 0.01.
5
In the BRCA2 clinical-history likelihood-ratio dataset, this variant has an LR of 0.9916 in 1 proband, which is within the neutral zone and does not support PP4 or BP5.
Final determination: Under ENIGMA BRCA1/BRCA2 Specification Table 3, one strong pathogenic criterion (PS3_Strong) together with at least two supporting pathogenic criteria supports a Likely Pathogenic classification.
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 missense variant is in the BRCA2 DNA-binding domain (amino acids 2481-3186), where ENIGMA applies BP4 only when BayesDel no-AF is less than or equal to 0.18 and SpliceAI is less than or equal to 0.1. SpliceAI is low at 0.01, but BayesDel is 0.421539, which is above the benign threshold and does not support BP4.
cspec bayesdel spliceai vcep_specifications_v1_2_2024_11_18
PP1 Not assessed No segregation data were identified to show co-segregation of this variant with disease in affected relatives, so PP1 cannot be assessed from the available evidence.
cspec vcep_specifications_v1_2_2024_11_18
BS1 Not met This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not meet the ENIGMA BRCA2 BS1 frequency threshold of filter allele frequency greater than 0.00002 for supporting or greater than 0.0001 for strong benign evidence.
cspec gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18
PM3 Not assessed No evidence was identified that this variant was observed in trans with another BRCA2 variant in an individual with a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 cannot be assessed.
cspec vcep_specifications_v1_2_2024_11_18
PM2 Met This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is consistent with rarity in population controls and supports PM2 at supporting strength under the ENIGMA BRCA2 framework.
cspec gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18
PP4 Not met In the BRCA2 clinical-history likelihood-ratio resource, this variant has an LR of 0.9916 in 1 proband. This value is within the neutral zone between 0.48 and 2.08 and therefore does not support PP4.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP3 N/A BP3 is not applicable in the ENIGMA BRCA2 specification for this gene framework.
cspec
PVS1 N/A This is a missense substitution rather than a nonsense, frameshift, canonical splice-site, initiation-codon, or exon-level loss-of-function variant. SpliceAI predicts no meaningful splice disruption with a maximum delta score of 0.01, so available evidence does not support applying PVS1.
cspec pvs1_gene_context pvs1_variant_assessment spliceai vcep_specifications_v1_2_2024_11_18
PM1 N/A PM1 is not applied in the ENIGMA BRCA2 specification for this gene framework, even for variants within important domains.
cspec vcep_specifications_v1_2_2024_11_18
PP5 Met Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.
cspec clinvar
BS2 Not assessed No qualifying evidence was identified showing this variant in individuals without a Fanconi anemia phenotype under the ENIGMA BRCA2 BS2 scoring framework, so BS2 cannot be assessed.
cspec vcep_specifications_v1_2_2024_11_18
BP1 Not met This missense variant is within the BRCA2 DNA-binding domain at residue 2562, and ENIGMA applies BP1_Strong only to silent, missense, or in-frame variants outside clinically important domains with no predicted splice effect. Although SpliceAI is low at 0.01, the domain criterion for BP1 is not met.
cspec spliceai vcep_specifications_v1_2_2024_11_18
BS4 Not assessed No quantitative non-segregation data were identified to show lack of segregation with disease in affected relatives, so BS4 cannot be assessed.
cspec vcep_specifications_v1_2_2024_11_18
BS3 Not met Available calibrated functional evidence does not show normal protein function. In the ENIGMA BRCA functional assay table, this variant is assigned PS3_Strong rather than BS3, so BS3 is not supported.
cspec vcep_specifications_table9_v1_2_2024_11_18 PMID:33609447
PS1 Not assessed No evidence was identified that a previously classified pathogenic or likely pathogenic variant causes the same amino acid change or the same splicing effect, so PS1 cannot be assessed from the available evidence.
cspec vcep_specifications_v1_2_2024_11_18
BP7 N/A BP7 is intended for synonymous or certain intronic variants without splice impact and is not applicable to this missense substitution.
cspec spliceai vcep_specifications_v1_2_2024_11_18
BA1 Not met This variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not approach the ENIGMA BRCA2 BA1 threshold of filter allele frequency greater than 0.001.
cspec gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18
PM5 N/A In the ENIGMA BRCA2 framework, PM5 is repurposed for truncating or protein-termination variants rather than classic same-residue missense logic. Because this is a missense substitution, PM5 is not applicable.
cspec pm5_candidates vcep_specifications_table4_v1_2_2024_11_18
BP5 Not met In the BRCA2 clinical-history likelihood-ratio resource, this variant has an LR of 0.9916 in 1 proband. This value is above the BP5 supporting threshold of 0.48 and therefore does not support BP5.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PS3 Met In a calibrated BRCA2 functional study summarized in the ENIGMA functional assay table, this variant showed protein function similar to pathogenic control variants, and the ENIGMA resource assigns PS3 at strong strength.
cspec vcep_specifications_table9_v1_2_2024_11_18 PMID:33609447
PM6 N/A PM6 is not applicable in the ENIGMA BRCA2 specification for this gene framework.
cspec
PS4 Not assessed No case-control dataset or other quantitative evidence was identified showing that this variant is significantly enriched in affected individuals compared with controls, so PS4 cannot be assessed.
cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PM4 N/A PM4 is not applicable in the ENIGMA BRCA2 specification for this gene framework.
cspec
BP6 N/A BP6 is not applicable in the ENIGMA BRCA2 specification for this gene framework.
cspec
PS2 N/A PS2 is not applicable in the ENIGMA BRCA2 specification for this gene framework.
cspec
PP3 Met This missense variant lies in the BRCA2 DNA-binding domain, and BayesDel no-AF is 0.421539, which is above the ENIGMA PP3 threshold of 0.30. REVEL is also high at 0.921, while SpliceAI is low at 0.01, supporting a damaging protein effect rather than a splice effect; together these findings support PP3 at supporting strength.
cspec bayesdel revel spliceai vcep_specifications_v1_2_2024_11_18
PP2 N/A PP2 is not applicable in the ENIGMA BRCA2 specification for this gene framework.
cspec
BP2 N/A BP2 is not applicable in the ENIGMA BRCA2 specification for this gene framework.
cspec
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