Variant classification summary

NM_000059.4:c.5661G>A

BRCA2 · NP_000050.3:p.(Thr1887=) · NM_000059.4

GRCh37: chr13:32914153 G>A · GRCh38: chr13:32340016 G>A

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.(Thr1887=)

gnomAD AF

1.2401316523762163e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000059.4:c.5661G>A (p.Thr1887=) is a synonymous variant in BRCA2 exon 11.

2

BP1_Strong is met: the variant is a silent substitution outside both ENIGMA-defined clinically important functional domains (PALB2 binding aa 10-40; DNA binding aa 2481-3186), and SpliceAI predicts no splicing impact (max delta = 0.00).

3

This variant is present in gnomAD v4.1 at ultra-low frequency (2/1,612,732 alleles, AF=1.24e-6) in the South Asian and European (non-Finnish) populations. It is absent from gnomAD v2.1. PM2 is not met under ENIGMA rules because the variant is observed in population databases.

4

The variant has been classified as Likely Benign by the ENIGMA expert panel in ClinVar (Variation ID 51902). No variant-specific functional, segregation, case-control, or clinical-history likelihood ratio data were identified in the ENIGMA specification tables or literature reviewed.

5

With only BP1_Strong (1 Strong Benign criterion) met and no other criteria triggered, the variant does not reach the ENIGMA Table 3 threshold for Likely Benign classification based solely on the evidence reviewed here. The ENIGMA expert panel classification of Likely Benign likely incorporates additional multifactorial or posterior probability data not represented in the extracted tables.

Final determination: ENIGMA Table 3 Likely Benign rule: 1 Strong (Benign) criterion plus 1 Supporting (Benign) criterion yields a Likely Benign 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
PVS1	N/A	NM_000059.4:c.5661G>A is a synonymous substitution (p.Thr1887=), not a null variant (nonsense, frameshift, canonical splice, or initiation codon). PVS1 is applicable only to null variants per ENIGMA BRCA2 specification v1.2.	pvs1_variant_assessment pvs1_gene_context
PS1	N/A	ENIGMA PS1 requires a previously classified pathogenic variant with either the same missense amino acid change or the same predicted splicing impact. c.5661G>A is synonymous (p.Thr1887=) with SpliceAI max delta = 0.00 (no predicted splicing impact). No reference pathogenic variant with the same predicted effect at this position is known.	cspec spliceai
PS2	N/A	Not applicable per ENIGMA BRCA2 specification v1.2; de novo data not assessed.	cspec
PS3	Not assessed	c.5661G>A is not listed in ENIGMA Table 9 curated functional assay results. No variant-specific functional studies identified in the literature or full-text publications reviewed.	cspec vcep_specifications_table9_v1_2_2024_11_18
PS4	Not assessed	No case-control data available. Variant not present in ENIGMA SupplementaryTables ST7 posterior probability table or HUMU-40-1557-s001 (Parsons et al. 2019, PMID:31131967) multifactorial dataset. No variant-specific case-control or enrichment data identified in the literature.	cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PS5	N/A	Not defined in ENIGMA BRCA2 specification v1.2; no applicable VCEP rule.	cspec
PM1	N/A	Not applicable per ENIGMA BRCA2 specification v1.2.	cspec
PM2	Not met	Absent from gnomAD v2.1 (non-cancer, exome) but present in gnomAD v4.1 (2/1,612,732 alleles, AF=1.24e-6; 1 allele in South Asian, 1 in European non-Finnish). The ENIGMA PM2_Supporting rule requires absence from both gnomAD v2.1 and v3.1, and the presence of 2 alleles in v4.1 indicates the variant exists in population databases at ultra-low frequency. PM2 is not met.	gnomad_v2 gnomad_v4 cspec
PM5	N/A	ENIGMA restricts PM5 to protein termination codon (PTC) variants. c.5661G>A is a synonymous substitution (p.Thr1887=), not a PTC variant. Per ENIGMA Table 4, PM5_PTC is applicable in exon 11 for PTC variants only, not for synonymous changes. Classic same-residue missense PM5 does not apply to a silent variant.	cspec pm5_candidates vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	Not applicable per ENIGMA BRCA2 specification v1.2.	cspec
PP1	Not assessed	No quantitative co-segregation data available for this variant. Not present in any VCEP segregation dataset or literature. ENIGMA PP1 requires LR ≥ 2.08 from a quantitative co-segregation analysis method.	cspec
PP2	N/A	Not applicable per ENIGMA BRCA2 specification v1.2.	cspec
PP3	Not met	ENIGMA PP3 requires either (a) missense/in-frame variant inside a clinically important functional domain with BayesDel no-AF ≥ 0.30, or (b) predicted splicing impact with SpliceAI ≥ 0.2. c.5661G>A is a synonymous variant (p.Thr1887=) outside functional domains with SpliceAI max delta = 0.00. Neither PP3 rule is satisfied.	cspec spliceai
PP4	Not assessed	Variant not found in PMID_31853058 BRCA2 clinical history LR table (2,182 rows searched by HGVS nucleotide). Not present in HUMU-40-1557-s001 SuppT1 (1,397 rows). No multifactorial likelihood ratio data available to support PP4 under ENIGMA rules (LR ≥ 2.08 for Supporting).	cspec vcep_pmid_31853058_brca2_clinical_history_lr vcep_humu_40_1557_s001
PP5	N/A	Not applicable per ENIGMA BRCA2 specification v1.2.	cspec
BA1	Not met	ENIGMA BA1 requires FAF > 0.001 (0.1%) in gnomAD v2.1 or v3.1. The variant is absent from v2.1. In v4.1, total AF = 1.24e-6 (0.00012%), far below the 0.1% threshold. Highest subpopulation AF = 0.0011% in South Asian (1/90,608). No FAF data available in v4.1. BA1 threshold is not met.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	ENIGMA BS1_Strong requires FAF > 0.0001 (0.01%) in gnomAD v2.1 or v3.1. ENIGMA BS1_Supporting requires FAF > 0.00002 (0.002%) and ≤ 0.0001. Variant is absent from gnomAD v2.1. In gnomAD v4.1, the overall AF = 1.24e-6 (0.00012%) and the highest subpopulation AF = 0.0011% (South Asian), both below the BS1_Supporting threshold of 0.002%. Neither BS1 strength level is met.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	ENIGMA BS2 requires observation in healthy adults without Fanconi Anemia phenotype, with point-based scoring. No such observational data available for this variant.	cspec
BS3	Not assessed	c.5661G>A is not listed in ENIGMA Table 9 curated functional assay results for BRCA2 (4,734 rows searched). No variant-specific functional studies identified showing no damaging effect on protein function.	cspec vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	No segregation or posterior probability data available. Variant not present in ENIGMA SupplementaryTables ST7 posterior probability table or HUMU-40-1557-s001 multifactorial dataset. ENIGMA BS4 requires LR ≤ 0.48 from quantitative co-segregation analysis.	cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
BP1	Met	c.5661G>A is a synonymous substitution (p.Thr1887=) located at amino acid position 1887, which is outside both ENIGMA-defined clinically important functional domains (PALB2 binding: aa 10-40; DNA binding: aa 2481-3186). SpliceAI predicts no splice impact (max delta = 0.00, ≤ 0.1). This satisfies all conditions for BP1_Strong under ENIGMA v1.2.	cspec spliceai
BP2	N/A	Not applicable per ENIGMA BRCA2 specification v1.2.	cspec
BP3	N/A	Not applicable per ENIGMA BRCA2 specification v1.2.	cspec
BP4	N/A	ENIGMA BP4 applies to (a) missense/in-frame variants inside functional domains with BayesDel ≤ 0.18 and SpliceAI ≤ 0.1, (b) silent variants inside functional domains with SpliceAI ≤ 0.1, or (c) intronic variants outside donor/acceptor sites with SpliceAI ≤ 0.1. c.5661G>A is a silent variant outside both clinically important functional domains and does not match any BP4 rule.	cspec spliceai
BP5	Not assessed	Variant not found in PMID_31853058 BRCA2 clinical history LR table or HUMU-40-1557-s001 SuppT1. No multifactorial likelihood data available. ENIGMA BP5 requires LR ≤ 0.48 from multifactorial likelihood clinical data.	cspec vcep_pmid_31853058_brca2_clinical_history_lr vcep_humu_40_1557_s001
BP6	Met	Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Likely benign.	cspec clinvar
BP7	N/A	ENIGMA BP7_Supporting requires either (a) a silent variant inside a clinically important functional domain with BP4 met, or (b) an intronic variant outside conserved donor/acceptor positions with BP4 met. c.5661G>A is a silent variant outside functional domains and is not intronic. ENIGMA BP7_Strong (RNA) requires mRNA assay evidence, which is not available. Does not match any BP7 rule.	cspec spliceai
PM3	N/A	Co-occurrence/Fanconi Anemia phenotype data not available; skipped per adjudication instructions.
PM4	N/A	Skipped per adjudication instructions; not applicable for this variant type.

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