Variant classification summary

NM_000059.4:c.7317A>G

BRCA2 · NP_000050.3:p.(Gly2439=) · NM_000059.4

GRCh37: chr13:32929307 A>G · GRCh38: chr13:32355170 A>G

Gene: BRCA2 Transcript: NM_000059.4

Final call

Likely Benign

BP1 strong (benign) BP6 supporting (benign)

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Gly2439=)

gnomAD AF

3.531931136017766e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP1 (Strong): synonymous change at codon 2439, outside the PALB2-binding and DNA-binding domains, with no predicted splice impact (SpliceAI max delta 0.012).

2

BP6 (Supporting): ENIGMA expert panel classified this exact variant Likely benign (ClinVar SCV000579037).

3

Likely Benign: ENIGMA CSPEC v1.2 Table 3 combines BP1 (Strong) with BP6 (Supporting), both benign-direction, with no pathogenic criteria met.

Final determination: ENIGMA BRCA1/BRCA2 CSPEC v1.2 Table 3 Likely Benign rule: 1 Strong (Benign) + 1 Supporting (Benign) criterion = Likely Benign; here BP1 (Strong, benign) plus BP6 (Supporting, benign) satisfy this combination with no competing pathogenic evidence.

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	Not applicable: a synonymous change (p.(Gly2439=)) is not a null variant such as nonsense, frameshift, or splice-site disruption.	cspec spliceai
PS1	N/A	Not applicable: PS1 requires a missense or splice-impacting variant; this synonymous change (p.(Gly2439=)) is neither.	cspec spliceai
PS2	N/A	Not applicable: the ENIGMA BRCA2 specification designates PS2 (de novo) as not used.	cspec
PS3	Not assessed	Insufficient evidence: no functional assay result (minigene, saturation genome editing, or protein-based) for this variant was available.
PS4	Not assessed	Insufficient evidence: no case-control enrichment study reporting this exact variant was available.	cspec vcep_humu_40_1557_s001
PM1	N/A	Not applicable: the ENIGMA BRCA2 specification defines no PM1 hotspot rule for this gene.	cspec
PM2	Not met	Not met: the variant is present in gnomAD v2.1 (7/251,214 alleles; AF 2.8e-05), so the PM2 absence-from-controls requirement is not satisfied.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Insufficient evidence: no Fanconi anemia phenotype, second BRCA2 variant, or inheritance data were available to assess PM3.	cspec
PM4	N/A	Not applicable: the synonymous change leaves the protein sequence and length unchanged (p.(Gly2439=)).	cspec
PM5	N/A	Not applicable: PM5 applies to protein-termination or missense changes; this variant is synonymous.	cspec
PM6	N/A	Not applicable: the ENIGMA BRCA2 specification designates PM6 (de novo) as not used.	cspec
PP1	Not assessed	Insufficient evidence: no family segregation data or quantitative co-segregation likelihood ratio were available.	cspec
PP2	N/A	Not applicable: the ENIGMA BRCA2 specification defines no PP2 rule for this gene.	cspec
PP3	Not met	Not met: SpliceAI max delta 0.012 is far below the ≥0.2 PP3 splice-impact threshold for silent variants.	spliceai cspec vcep_specifications_v1_2_2024_11_18
PP4	Not assessed	Insufficient evidence: no ENIGMA multifactorial clinical-history likelihood ratio for this variant was available.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5	Not met	Not met: the sole ClinVar expert-panel entry is ENIGMA Likely benign, not Pathogenic or Likely pathogenic.	clinvar
BA1	Not met	Not met: maximum gnomAD non-founder FAF is 1.687e-05, far below the >0.001 BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 maximum population FAF 1.687e-05 falls below the BS1 Supporting lower bound of 0.00002.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Insufficient evidence: no identifiable healthy adult probands or co-occurrence variables were available to assign BS2 points.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Insufficient evidence: no functional assay demonstrating a benign effect for this variant was available.
BS4	Not assessed	Insufficient evidence: no family testing showing lack of segregation with disease was available.	cspec
BP1	Met	Met (Strong): silent change at codon 2439, outside the PALB2-binding (aa10-40) and DNA-binding (aa2481-3186) domains, with SpliceAI max delta 0.012 ≤ 0.1.	cspec spliceai
BP2	N/A	Not applicable: the ENIGMA BRCA2 specification designates BP2 as not used.	cspec
BP3	N/A	Not applicable: the ENIGMA BRCA2 specification designates BP3 as not used for this gene.	cspec
BP4	Not met	Not met: SpliceAI is benign (max delta 0.012 ≤ 0.1), but BP4's silent-variant rule requires a position inside a functional domain; codon 2439 lies outside both.	spliceai cspec vcep_specifications_v1_2_2024_11_18
BP5	Not assessed	Insufficient evidence: no ENIGMA likelihood ratio against pathogenicity for this variant was available.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6	Met	Met (Supporting): ENIGMA expert panel classified this exact variant Likely benign (ClinVar SCV000579037).	clinvar
BP7	Not met	Not met: BP7 requires a silent variant inside a functional domain with BP4 met; codon 2439 lies outside both domains.	spliceai cspec vcep_specifications_v1_2_2024_11_18

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.