Variant classification summary

NM_000059.4:c.3073A>G

BRCA2 · NP_000050.3:p.(Lys1025Glu) · NM_000059.4

GRCh37: chr13:32911565 A>G · GRCh38: chr13:32337428 A>G

Gene: BRCA2 Transcript: NM_000059.4

Final call

Likely Benign

BP1 strong BS1 supporting BS4 supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Lys1025Glu)

gnomAD AF

5.3312834755008925e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP1 (Strong): missense change outside both clinically important BRCA2 domains with no predicted splice impact (SpliceAI max delta 0.00).

2

BS1 (Supporting): gnomAD allele frequency 5.795e-05 in v4.1 falls within the 0.00002-0.0001 supporting range.

3

BS4 (Supporting): ENIGMA segregation likelihood ratio 0.445 meets the <=0.48 threshold, favoring lack of cosegregation.

4

Overall Likely Benign: BP1_Strong plus BS1 and BS4 Supporting satisfies the one-Strong-plus-one-Supporting benign combination rule (ENIGMA score -6).

Final determination: Under ENIGMA BRCA2 v1.2 Table 3, one Strong (Benign) criterion plus one Supporting (Benign) criterion yields a Likely Benign classification; the total benign point score of -6 independently falls in the Likely Benign range.

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	Not met	Not met: c.3073A>G is a missense (p.Lys1025Glu), not a null variant, and SpliceAI max delta 0.00 indicates no damaging transcript effect.	cspec spliceai PMID:32599251
PS1	Not assessed	Not assessed: no previously classified pathogenic BRCA2 variant producing the same amino-acid change (p.Lys1025Glu) was documented.	cspec
PS2	N/A	Not applicable: the ENIGMA BRCA2 specification designates PS2 as not applicable, and no confirmed de novo observation exists.	cspec
PS3	Not assessed	Not assessed: no calibrated functional assay evidence exists, and this variant has no entry in the ENIGMA Table 9 functional data.	cspec vcep_specifications_table9_v1_2_2024_11_18 PMID:32599251
PS4	Not met	Not met: no case-control enrichment was identified, and the ENIGMA multifactorial record lacks a case-control LR for this exact variant.	cspec vcep_humu_40_1557_s001
PM1	N/A	Not applicable: ENIGMA BRCA2 does not apply PM1 independently, and Lys1025 lies outside the key domains in a missense coldspot.	cspec PMID:31911673
PM2	Not met	Not met: the variant is observed in gnomAD non-cancer controls (86/1,613,120 alleles in v4.1), so it is not absent as required.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no Fanconi anemia phenotype or second pathogenic BRCA2 variant is documented, so PM3 could not be applied.	cspec PMID:32599251
PM4	N/A	Not applicable: this is a single-amino-acid missense substitution, not an in-frame insertion/deletion or stop-loss change.	cspec
PM5	N/A	Not applicable: PM5 applies only to protein-termination variants in BRCA2, and c.3073A>G is a missense.	cspec
PM6	N/A	Not applicable: the ENIGMA BRCA2 specification designates PM6 as not applicable.	cspec
PP1	Not met	Not met: segregation likelihood ratio 0.445 is below the >=2.08 supporting threshold and favors lack of cosegregation.	cspec vcep_humu_40_1557_s001
PP2	N/A	Not applicable: the ENIGMA BRCA2 v1.2 specification explicitly marks PP2 as not applicable.	cspec
PP3	Not met	Not met: p.Lys1025Glu is outside the clinically important BRCA2 domains, and SpliceAI max delta 0.00 is below the >=0.20 threshold.	cspec spliceai bayesdel PMID:32599251
PP4	Not met	Not met: the ENIGMA multifactorial likelihood ratio of 2.035 is below the >=2.08 PP4 supporting threshold.	cspec vcep_humu_40_1557_s001 vcep_pmid_31853058_brca2_clinical_history_lr PMID:32599251
PP5	Not met	Not met: ClinVar has no expert-panel Pathogenic or Likely pathogenic submission for this exact variant.	clinvar
BA1	Not met	Not met: maximum allele frequency 5.795e-05 in gnomAD is below the BA1 threshold of >0.001.	cspec gnomad_v2 gnomad_v4
BS1	Met	Met (Supporting): the highest gnomAD allele frequency, 5.795e-05, falls within the ENIGMA supporting range of 0.00002 to 0.0001.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD provides no adult health status, age, or penetrance follow-up data needed to assess BS2.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no calibrated functional assay showing a benign effect exists, and this variant is absent from ENIGMA Table 9.	cspec vcep_specifications_table9_v1_2_2024_11_18 PMID:32599251
BS4	Met	Met (Supporting): segregation likelihood ratio 0.445 meets the <=0.48 supporting threshold for lack of segregation.	cspec vcep_humu_40_1557_s001
BP1	Met	Met (Strong): missense change outside both clinically important BRCA2 domains with no predicted splice impact (SpliceAI delta 0.00).	cspec spliceai
BP2	N/A	Not applicable: the ENIGMA BRCA2 v1.2 specification designates BP2 as not applicable.	cspec
BP3	N/A	Not applicable: BP3 applies to in-frame insertions/deletions in repetitive regions, not to this missense substitution.	cspec
BP4	Not met	Not met: BP4 requires location inside a clinically important domain, and p.Lys1025Glu is outside both.	cspec spliceai bayesdel
BP5	Not met	Not met: the ENIGMA multifactorial likelihood ratio of 2.035 is above the <=0.48 BP5 supporting threshold.	cspec vcep_humu_40_1557_s001 vcep_pmid_31853058_brca2_clinical_history_lr
BP6	Not met	Not met: ClinVar has no expert-panel Benign or Likely benign submission for this exact variant.	clinvar
BP7	Not assessed	Not assessed: no variant-specific RNA splicing assay is available, and BP7 supporting applies only to silent variants.	cspec PMID:32599251

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.