Variant classification summary

NM_000059.4:c.2133C>T

BRCA2 · NP_000050.3:p.(Cys711=) · NM_000059.4

GRCh37: chr13:32910625 C>T · GRCh38: chr13:32336488 C>T

Gene: BRCA2 Transcript: NM_000059.4

Final call

Likely Benign

BP1 strong (benign) BP4 supporting (benign) BP6 supporting (benign) BP7 supporting (benign)

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Cys711=)

gnomAD AF

1.301120078513303e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP1 (Strong): silent substitution outside clinically important functional domains (PALB2 binding aa 10-40, DNA binding aa 2481-3186) with no predicted splice impact (SpliceAI max delta 0.011 ≤0.1).

2

BP4 (Supporting): SpliceAI max delta 0.011 meets the ≤0.1 no-splicing-impact threshold for silent variants.

3

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

4

BP7 (Supporting): silent variant with no predicted splice impact; no mRNA assay data were available to elevate to Strong.

5

Overall: Likely Benign — no pathogenic-direction criteria met; BP1 (Strong) plus three Supporting benign codes satisfy the VCEP rule 1 Strong (Benign) + ≥1 Supporting (Benign).

Final determination:

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: synonymous change with no predicted splice impact (SpliceAI max delta 0.01), so no null-variant pathway applies.	cspec spliceai
PS1	N/A	Not applicable: no amino acid change occurs and SpliceAI max delta 0.01 predicts no splicing impact, so no PS1 pathway applies.	cspec spliceai
PS2	N/A	Not applicable under the ENIGMA BRCA1/BRCA2 VCEP specification for BRCA2.	cspec
PS3	Not assessed	Not assessed: no variant-specific functional assay results were identified, so insufficient evidence was available.
PS4	Not assessed	Not assessed: no exact-variant case-control study meeting the ENIGMA threshold (p≤0.05, OR≥4) was identified.	cspec PMID:22970155
PM1	N/A	Not applicable: this VCEP marks PM1 Not Applicable for BRCA2; domain evidence is handled through other criteria.	cspec
PM2	Not met	Not met: observed in gnomAD (11/251,022 alleles; grpmax FAF 0.00029), so not absent from population controls.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no Fanconi-anemia proband observation, second BRCA2 variant, or phase data were available.	cspec
PM4	N/A	Not applicable: synonymous change does not alter protein length or the stop codon.
PM5	N/A	Not applicable: reserved for PTC-comparator logic; this synonymous change is not a protein-termination or missense variant.	cspec pm5_candidates vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	Not applicable under the ENIGMA BRCA1/BRCA2 VCEP specification for BRCA2.	cspec
PP1	Not assessed	Not assessed: no family genotype and phenotype data or co-segregation likelihood ratio was available.	cspec
PP2	N/A	Not applicable: marked Not Applicable for BRCA2 in this VCEP; the variant is also synonymous, not missense.	cspec
PP3	Not met	Not met: SpliceAI max delta 0.011, far below the ≥0.2 threshold required for silent variants.	cspec spliceai
PP4	Not assessed	Not assessed: no calibrated multifactorial likelihood ratio toward pathogenicity (LR ≥2.08) was available.	cspec PMID:31853058 vcep_pmid_31853058_brca2_clinical_history_lr
PP5	Not met	Not met: the ClinVar expert-panel assertion is Likely benign, not Pathogenic/Likely pathogenic, so it cannot support PP5.	clinvar
BA1	Not met	Not met: gnomAD grpmax FAF 0.00029, below the BA1 threshold of >0.001.	cspec gnomad_v2 gnomad_v4
BS1	Not assessed	Not assessed: FAF 0.00029 exceeds the BS1_Strong threshold of >0.0001, but the required gnomAD non-cancer subset was not documented.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no observations in individuals without Fanconi anemia were available; absence of homozygotes alone is insufficient.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific functional assay result was identified; the SpliceAI prediction is bioinformatic only and cannot substitute.
BS4	Not assessed	Not assessed: no quantitative evidence of non-segregation in affected family members was available.	cspec
BP1	Met	Met (Strong): silent substitution outside clinically important functional domains (aa 10-40, 2481-3186) with no predicted splice impact (SpliceAI max delta 0.011 ≤0.1).	cspec spliceai
BP2	N/A	Not applicable: designated Not Applicable for BRCA2 in the ENIGMA v1.2 specification.	cspec
BP3	N/A	Not applicable: designated Not Applicable for BRCA2; also irrelevant to a single-nucleotide synonymous substitution.	cspec
BP4	Met	Met (Supporting): SpliceAI max delta 0.011, below the ≤0.1 no-splicing-impact threshold for silent variants.	cspec spliceai
BP5	Not assessed	Not assessed: no calibrated multifactorial likelihood ratio against pathogenicity (LR ≤0.48) was available.	cspec PMID:31853058 vcep_pmid_31853058_brca2_clinical_history_lr
BP6	Met	Met (Supporting): ENIGMA expert panel classified this exact variant as Likely benign.	clinvar
BP7	Met	Met (Supporting): silent variant with no predicted splice impact; no mRNA assay data were available to elevate to Strong.	cspec spliceai

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.